Cytokine : Hormone interrelationship R A Holding DO

April 2005 Ark International Training Seminars Cell communication - The basis of life For the smooth operation of all physiological processes in the organism, all of the approximately 60 trillion cells of the body need to be able to communicate. For the smooth operation of all physiological processes in the organism, all of the approximately 60 trillion cells of the body need to be able to communicate. This complex communication occurs via two chemical substances:- This complex communication occurs via two chemical substances:- CytokinesCytokines Cell surface molecules.Cell surface molecules.

April 2005 Ark International Training Seminars Cell communication - The basis of life This communication occurs as a: This communication occurs as a: direct communication:direct communication: adhesion molecules (cell-to-cell contact) adhesion molecules (cell-to-cell contact) indirect communication:indirect communication: cytokines (messenger substances) bound to specific receptor sites. cytokines (messenger substances) bound to specific receptor sites. These types of communication take place concomitantly and may also have an influence on one another. These types of communication take place concomitantly and may also have an influence on one another.

April 2005 Ark International Training Seminars Immune and endocrine system reciprocity The cells of immune and neuroendocrine systems share signal molecules and receptors The cells of immune and neuroendocrine systems share signal molecules and receptors Both hormones and neuropeptides alter function of the immune system Both hormones and neuropeptides alter function of the immune system Immune system is innervated by noradrenergic sympathetic nerve cells that have direct contact with lymphocytes and macrophages Immune system is innervated by noradrenergic sympathetic nerve cells that have direct contact with lymphocytes and macrophages In turn, the immune system-derived cytokines influence the function of both neural and endocrine systems In turn, the immune system-derived cytokines influence the function of both neural and endocrine systems

April 2005 Ark International Training Seminars Stress, physiology & function

April 2005 Ark International Training Seminars Overview of inflammation: Local inflammatory response Local inflammatory response Macrophages and monocytes initiate acute phase response (APR)Macrophages and monocytes initiate acute phase response (APR) The APR initiates 1 st phase of inflammatory cytokinesThe APR initiates 1 st phase of inflammatory cytokines IL-1 IL-1 TNF- TNF- They activate the 2 nd phase of cytokines that augment the shift in balance necessary for the inflammatory responseThey activate the 2 nd phase of cytokines that augment the shift in balance necessary for the inflammatory response IL-12 IL-12 INF- INF- INF- INF- GM-CSF (Granulocyte-Macrophage Colony Stimulating Factor) GM-CSF (Granulocyte-Macrophage Colony Stimulating Factor) Fibroblast growth factor Fibroblast growth factor

April 2005 Ark International Training Seminars Hormonal stimulation of pro-inflammatory cytokines

April 2005 Ark International Training Seminars Control of the immune reaction The specific control of the sequence of the activating and the suppressive steps in the of the immune response is mediated by the immune cells through the release of both pro- inflammatory and anti-inflammatory cytokines. The specific control of the sequence of the activating and the suppressive steps in the of the immune response is mediated by the immune cells through the release of both pro- inflammatory and anti-inflammatory cytokines. The ratio of Th1 (pro-inflammatory) and Th2 (anti- inflammatory) cells and their cytokines is clinically important. The ratio of Th1 (pro-inflammatory) and Th2 (anti- inflammatory) cells and their cytokines is clinically important. They balance each other by inhibiting each other and stimulating their own responseThey balance each other by inhibiting each other and stimulating their own response

April 2005 Ark International Training Seminars Pro-inflammatory Th1 cells and their cytokines Th1 cells are pro-inflammatory and are a response to intracellular organisms such as viruses, bacteria and some parasites Th1 cells are pro-inflammatory and are a response to intracellular organisms such as viruses, bacteria and some parasites Inhibition of Th1 leads to failure to respond to infection and to kill cancer cells Inhibition of Th1 leads to failure to respond to infection and to kill cancer cells Chronic stimulation of Th1 leads to autoimmune disease and chronic inflammation Chronic stimulation of Th1 leads to autoimmune disease and chronic inflammation Th1 dominant diseases include: Th1 dominant diseases include: Hashmoto’s diseaseHashmoto’s disease Type 1 diabetesType 1 diabetes Multiple SclerosisMultiple Sclerosis Crohn’s diseaseCrohn’s disease SarcoidosisSarcoidosis These activating cytokines are: TNF, IL-1, IL-2, IL-6, IL- 12, IFN-, IFN-, TGF. These activating cytokines are: TNF, IL-1, IL-2, IL-6, IL- 12, IFN-, IFN-, TGF.

April 2005 Ark International Training Seminars Anti-inflammatory Th2 cells and their cytokines Th2 cells are anti-inflammatory and are a response to helminth parasites and allergens Th2 cells are anti-inflammatory and are a response to helminth parasites and allergens Chronic stimulation of Th2 leads to chronic allergic response and failure to respond to infection and cancer cells Chronic stimulation of Th2 leads to chronic allergic response and failure to respond to infection and cancer cells Th2 dominant diseases include: Th2 dominant diseases include: Allergies / atopyAllergies / atopy InflammationInflammation The Th2 or anti-inflammatory or suppressing cytokines are: IL-4, IL-5, IL-10, and to some extent IL-13 The Th2 or anti-inflammatory or suppressing cytokines are: IL-4, IL-5, IL-10, and to some extent IL-13

April 2005 Ark International Training Seminars Inflammatory triggers

April 2005 Ark International Training Seminars Control of the immune reaction The defensive posture can be: The defensive posture can be: excessive in partexcessive in part extreme antigen exposition extreme antigen exposition over-stimulation over-stimulation lacking counter regulation lacking counter regulation inhibited in partinhibited in part over-expression of immune complexes, cytokines and/or adhesion molecules). over-expression of immune complexes, cytokines and/or adhesion molecules). The over and under expression will impedes the immune functions or causes such systemic side effects as, for example, the wasting syndrome seen in HIV infections. The over and under expression will impedes the immune functions or causes such systemic side effects as, for example, the wasting syndrome seen in HIV infections. The immune system then recognises endogenous structures as being foreign (cross-reactions, insufficient tolerance). The immune system then recognises endogenous structures as being foreign (cross-reactions, insufficient tolerance). This is considered to be the cause of autoimmune diseases. The immune system can react excessively to harmless substances (insufficient tolerance) with the subsequent development of allergies.This is considered to be the cause of autoimmune diseases. The immune system can react excessively to harmless substances (insufficient tolerance) with the subsequent development of allergies.

April 2005 Ark International Training Seminars Types of cytokines The immune cells secrete numerous soluble and, in part, highly specialised mediators which, in a series of complex interactions, guarantee for the viability, development, differentiation, proliferation and activity in the organism. The immune cells secrete numerous soluble and, in part, highly specialised mediators which, in a series of complex interactions, guarantee for the viability, development, differentiation, proliferation and activity in the organism. These cytokines are soluble glycoproteins that function as intercellular signalling molecules. These cytokines are soluble glycoproteins that function as intercellular signalling molecules. The other three intercellular signalling molecules are neurotransmitters, endocrine hormones and autacoidsThe other three intercellular signalling molecules are neurotransmitters, endocrine hormones and autacoids

April 2005 Ark International Training Seminars Cytokines Cytokines have an effect on all cells (not only on the immune cells). Cytokines have an effect on all cells (not only on the immune cells). Cytokines maintain a rigidly controlled communication network between the individual cell types including those of the nervous system. Cytokines maintain a rigidly controlled communication network between the individual cell types including those of the nervous system. Cytokines are released in the course of normal cell functions, especially in response to particular stimulus: e.g. antigens, immune complexes, complement, enzymes, other cytokines. Cytokines are released in the course of normal cell functions, especially in response to particular stimulus: e.g. antigens, immune complexes, complement, enzymes, other cytokines.

April 2005 Ark International Training Seminars Control of the immune reaction In contrast to the reactions seen with many hormones, those attributed to cytokines usually only involve local, short-distance signals. In contrast to the reactions seen with many hormones, those attributed to cytokines usually only involve local, short-distance signals. Normally, their release is usually only necessary for a definite purpose, at a defined time and at a locally-limited site. Normally, their release is usually only necessary for a definite purpose, at a defined time and at a locally-limited site.

April 2005 Ark International Training Seminars

April 2005 Ark International Training Seminars Cellular inflammation: triggers Cell type Trigger B-lymphocyte ACTH, -endorphins, growth hormone, IGF-1 T-lymphocytes ACTH, -endorphins, growth hormone, IGF-1, prolactin, TSH Mast cells, eosinophils, neutrophils Kinins, vasoactive intestinal peptide, somatostatin

April 2005 Ark International Training Seminars Cellular inflammation: triggers Cell type Trigger Platelets Serotonin, PAF, neuropeptide-Y Splenocytes LH, FSH, CRH, prolactin Thymocytes CRH, LHRH, AVP, oxytocin Macrophages ACTH, -endorphins, growth hormone, substance P

April 2005 Ark International Training Seminars Cellular inflammation: neuroendocrine regulation CytokineEffect TNF type (TNF-, TNF-, IL-1) ↑ type 1 APR ↑ CRP ↑ serum amyloid protein ↓ type 2 APR IL-6 type (IL-6, IL-11) ↑ type 2 APR ↑ fibrinogen Corticosteroids ↑ APR Synergy with most cytokines Angiostatic Insulin ↓ cytokine effects FGF, TGF- ↓ cytokine effects

April 2005 Ark International Training Seminars TNF type cytokines TNF-, TNF-, IL-1) TNF-, TNF-, IL-1) They have the effect of increasing type 1 acute phase reactants (APR), increasing CRP and serum amyloid protein and decreasing type 2 APRThey have the effect of increasing type 1 acute phase reactants (APR), increasing CRP and serum amyloid protein and decreasing type 2 APR i.e. they assist in the pro-inflammatory responsei.e. they assist in the pro-inflammatory response They increase ACTHThey increase ACTH They have a variable effect on prolactin except for IL-6 that increases prolactinThey have a variable effect on prolactin except for IL-6 that increases prolactin They lower the production of growth hormone, TSH and LHThey lower the production of growth hormone, TSH and LH

April 2005 Ark International Training Seminars Hormonal effects on inflammation Corticosteroids increase acute phase reactants (APR), support the action of most cytokines and are angiostatic Corticosteroids increase acute phase reactants (APR), support the action of most cytokines and are angiostatic IL-1, IL-1, TNF-, IL-2 and IL-6 increases ACTH production IL-1, IL-1, TNF-, IL-2 and IL-6 increases ACTH production Insulin decreases the action of most cytokines Insulin decreases the action of most cytokines FGF and TGF-decrease theaction of most cytokines FGF and TGF-decrease theaction of most cytokines

April 2005 Ark International Training Seminars Cytokine & effects on hormones cytokineACTHprolactin Growth hormone TSHLHFSH IL-1 ?↕?↓↓↕ IL-1 ↑↕↓??? TNF- ↑↕↕ IL-2 ↑↑↓ IL-6 ↑↑↓ INF- ?↑ TGF- ?↑↑ PDGF ?↓?

April 2005 Ark International Training Seminars Overview of inflammation

April 2005 Ark International Training Seminars Most common stimuli for cytokine expression Stress Stress PsychologicalPsychological AllergiesAllergies Chemical toxicityChemical toxicity Toxic metal exposureToxic metal exposure Glycosylated proteinGlycosylated protein Chronic subclinical infectionChronic subclinical infection DysbiosisDysbiosis Radiation / electromagneticRadiation / electromagnetic TraumaTrauma Low oestrogen Low oestrogen

April 2005 Ark International Training Seminars General activity of cytokines Cytokines involved in acute inflammation Cytokines involved in acute inflammation TNF-, IL-1, IL-6, IL-8, IL-11TNF-, IL-1, IL-6, IL-8, IL-11 And other chemokines, G-CSF, and GM-CSFAnd other chemokines, G-CSF, and GM-CSF Cytokines involved in chronic inflammation Cytokines involved in chronic inflammation They can be subdivided into: -They can be subdivided into: - Cytokines mediating humoral responses Cytokines mediating humoral responses IL-4, IL-5, IL-6, IL-7, and IL-13IL-4, IL-5, IL-6, IL-7, and IL-13 Cytokines mediating cellular responses Cytokines mediating cellular responses IL-1, IL-2, IL-3, IL-4, IL-7, IL-9, IL-10, IL-12, interferon (IFN), transforming growth factor-ß (TGF), and tumour necrosis factor- and ß (TNF).IL-1, IL-2, IL-3, IL-4, IL-7, IL-9, IL-10, IL-12, interferon (IFN), transforming growth factor-ß (TGF), and tumour necrosis factor- and ß (TNF).

April 2005 Ark International Training Seminars Humeral versus cellular immunity Dominance of the humoral immunity IL-4, IL-5, IL-6, IL-7, and IL-13Increased production of IL-4, IL-5, IL-6, IL-7, and IL-13 IL-1, IL-2, IL-3, IL-4, IL-7, IL- 9, IL-10, IL-12, IFN, TGF-, and TNF- and ß.Decreased production of IL-1, IL-2, IL-3, IL-4, IL-7, IL- 9, IL-10, IL-12, IFN, TGF-, and TNF- and ß. Check for parasites and mycobacterium. Dominance of cellular immunity IL-1, IL-2, IL-3, IL-4, IL-7, IL-9, IL-10, IL-12, IFN, TGF-, and TNF- and ß.Increased production of IL-1, IL-2, IL-3, IL-4, IL-7, IL-9, IL-10, IL-12, IFN, TGF-, and TNF- and ß. IL-4, IL-5, IL-6, IL-7, and IL-13Decreased production of IL-4, IL-5, IL-6, IL-7, and IL-13 Check for viruses and bacteria.

April 2005 Ark International Training Seminars Pro-inflammatory or activating cytokines TNF-,TNF-, IL-1,IL-1, IL-2,IL-2, IL-6,IL-6, IL-12,IL-12, IFN-,IFN-, IFN-,IFN-, TGF.TGF.

April 2005 Ark International Training Seminars IL-1 comes mainly from macrophages and monocytes. IL-1 comes mainly from macrophages and monocytes. IL-1 is induced by micro-organisms, microbial products, antigens, inflammatory agents, plant lectins, lymphokines and certain chemicals IL-1 is induced by micro-organisms, microbial products, antigens, inflammatory agents, plant lectins, lymphokines and certain chemicals IL-1 activates the process known as the acute phase response. IL-1 activates the process known as the acute phase response. This response is characterised by production of a variety of hepatic proteins (e.g., C-reactive protein, serum amyloid A, fibrinogen, complement, alpha 1-antitrypsin)This response is characterised by production of a variety of hepatic proteins (e.g., C-reactive protein, serum amyloid A, fibrinogen, complement, alpha 1-antitrypsin) Pro-inflammatory cytokines

April 2005 Ark International Training Seminars IL-1 activates adhesion molecules on vascular endothelium. (VCAM) activates adhesion molecules on vascular endothelium. (VCAM) stimulates the production of IL-8 that activates neutrophils. stimulates the production of IL-8 that activates neutrophils. elicits the release of histamine from mast cells at the site of inflammation causing increased capillary permeability and vasodilatation. elicits the release of histamine from mast cells at the site of inflammation causing increased capillary permeability and vasodilatation. a potent mitogen for astroglial cells and induces astrocytes to synthesise NGF. a potent mitogen for astroglial cells and induces astrocytes to synthesise NGF. interferes powerfully with the hypothalamic-hypophyseal- gonadal axis (HHGA). interferes powerfully with the hypothalamic-hypophyseal- gonadal axis (HHGA). At the CNS level,At the CNS level, decrease plasma LH levels (Luteinising hormone), a phenomenon attributed to the inhibition of hypothalamic secretion of LHRH and LHRH gene expression. decrease plasma LH levels (Luteinising hormone), a phenomenon attributed to the inhibition of hypothalamic secretion of LHRH and LHRH gene expression.

April 2005 Ark International Training Seminars Effect of IL-1 & TNF-  on cartilage

April 2005 Ark International Training Seminars IL-2 Generated by T lymphocytes after stimulation by antigen or mitogen Generated by T lymphocytes after stimulation by antigen or mitogen Pro-inflammatory cytokine that plays a critical role in regulating both cellular and humoral chronic inflammatory responses. Pro-inflammatory cytokine that plays a critical role in regulating both cellular and humoral chronic inflammatory responses. Largely responsible for immunologic memory. Largely responsible for immunologic memory. The immune system forms a long-term "memory" from antigen exposure so that any future contact will stimulate an immediate defence against that particular antigen.The immune system forms a long-term "memory" from antigen exposure so that any future contact will stimulate an immediate defence against that particular antigen.

April 2005 Ark International Training Seminars IL-2 Influence the maturation and differentiation of lymphocytes in the thymus and bone marrow. Influence the maturation and differentiation of lymphocytes in the thymus and bone marrow. There are two major classes of lymphocytes: There are two major classes of lymphocytes: B lymphocytes (B cells) derived from the bone marrowB lymphocytes (B cells) derived from the bone marrow B cells express antibody molecules on their surface, and when stimulated by antigen, each B cell becomes a plasma cell that secretes antibodies specific for that antigen. B cells express antibody molecules on their surface, and when stimulated by antigen, each B cell becomes a plasma cell that secretes antibodies specific for that antigen. T-lymphocytes (T cells)T-lymphocytes (T cells)

April 2005 Ark International Training Seminars IL-2 T-lymphocytes (T cells) derived from bone marrow but matured by the thymus.T-lymphocytes (T cells) derived from bone marrow but matured by the thymus. T cells also express what appear to be antibody molecules on their surfaces, but unlike B cells, these molecules cannot be secreted T cells also express what appear to be antibody molecules on their surfaces, but unlike B cells, these molecules cannot be secreted T cells react to antigen stimulation by secreting other types of molecules; T cells react to antigen stimulation by secreting other types of molecules; cytotoxic ("killer") T cells secrete molecules that kill infected or abnormal cells on contact,cytotoxic ("killer") T cells secrete molecules that kill infected or abnormal cells on contact, "helper" T cells secrete a variety of cytokines involved in the immune response."helper" T cells secrete a variety of cytokines involved in the immune response. Thus, a foreign antigen stimulates both B cells and T cells, and the resulting immune response is specific for that antigen alone.Thus, a foreign antigen stimulates both B cells and T cells, and the resulting immune response is specific for that antigen alone.

April 2005 Ark International Training Seminars IL-2 After an antigen binds receptors on an individual T cell, the antigen stimulates the T cell to secrete IL-2 and to make IL-2 receptors. After an antigen binds receptors on an individual T cell, the antigen stimulates the T cell to secrete IL-2 and to make IL-2 receptors. The T lymphocyte has two receptor sites; The T lymphocyte has two receptor sites; the first site readily binds IL-2,the first site readily binds IL-2, the second site attaches more slowly to the IL-2 molecule.the second site attaches more slowly to the IL-2 molecule. It is the interaction at the second site, however, that activates the T cell, causing it to undergo complex changes in morphology, metabolism, expression of surface receptors, and the production of cytokines It is the interaction at the second site, however, that activates the T cell, causing it to undergo complex changes in morphology, metabolism, expression of surface receptors, and the production of cytokines

April 2005 Ark International Training Seminars IL-2 Stimulates the proliferation of B cells, helping them to secrete antibodies Stimulates the proliferation of B cells, helping them to secrete antibodies IL-2 stimulates production of Natural Killer T cells IL-2 stimulates production of Natural Killer T cells They represent the first line of defence against intracellular pathogens because of their immediate responsiveness to IL-2.They represent the first line of defence against intracellular pathogens because of their immediate responsiveness to IL-2. In synergy with IL-1.In synergy with IL-1. Il-2 has been found to be low in persistent microbial infections and cancer and there is a considerable body of research into the immuno-stimulatory effect of IL-2. Il-2 has been found to be low in persistent microbial infections and cancer and there is a considerable body of research into the immuno-stimulatory effect of IL-2.

April 2005 Ark International Training Seminars IL-2 ↑ lymphokine secretion ↑ lymphokine secretion In turn ↑ IFN-, lymphotoxin, IL-4, IL-3, IL-5, GM-CSF {macrophage colony stimulating factor})In turn ↑ IFN-, lymphotoxin, IL-4, IL-3, IL-5, GM-CSF {macrophage colony stimulating factor}) Enhanced expression of MHC (Major Histocompatability Complex) class II proteins Enhanced expression of MHC (Major Histocompatability Complex) class II proteins Stimulates fibroblasts to secrete extracellular matrix Stimulates fibroblasts to secrete extracellular matrix

April 2005 Ark International Training Seminars

April 2005 Ark International Training Seminars IL-6 Derived from macrophages, fibroblasts, bone marrow, vascular endothelium and some T cells, from IL-1 stimulated B cells, antigens, mitogens and endotoxins. Derived from macrophages, fibroblasts, bone marrow, vascular endothelium and some T cells, from IL-1 stimulated B cells, antigens, mitogens and endotoxins. Major derivation is from visceral adipose tissue (produce 2-3 times IL- 6 than depot fat cells); adipocytes are also producing oestrogen in post menopausal women Major derivation is from visceral adipose tissue (produce 2-3 times IL- 6 than depot fat cells); adipocytes are also producing oestrogen in post menopausal women Inhibits the macrophage production of IL-1 (a feedback loop) and IFN-. Inhibits the macrophage production of IL-1 (a feedback loop) and IFN-.

April 2005 Ark International Training SeminarsIL-6 Stimulates the production of immunoglobulin producing B cells Stimulates the production of immunoglobulin producing B cells Stimulates proliferation of thymic and peripheral T cells Stimulates proliferation of thymic and peripheral T cells With IL-1, IL-6 induces T cell differentiation to “Killer” T lymphocytes With IL-1, IL-6 induces T cell differentiation to “Killer” T lymphocytes Stimulates the liver to produce Acute Phase Proteins such as fibrinogen, serum amyloid protein A and 2- macroglobulin. Stimulates the liver to produce Acute Phase Proteins such as fibrinogen, serum amyloid protein A and 2- macroglobulin.

April 2005 Ark International Training SeminarsIL-6 Activates Natural Killer cells (NK cells). Activates Natural Killer cells (NK cells). Induces breakdown of the extracellular matrix Induces breakdown of the extracellular matrix Induction of osteoclastogenesis and osteoclast activity Induction of osteoclastogenesis and osteoclast activity involved with cell signalling in bone turnover, which leads to increased conversion of osteoblasts to osteoclasts and the reabsorption of boneinvolved with cell signalling in bone turnover, which leads to increased conversion of osteoblasts to osteoclasts and the reabsorption of bone Wong PK et al. The role of the interleukin-6 family of cytokines in inflammatory arthritis and bone turnover. Arthritis Rheum. 2003;48(5): Wong PK et al. The role of the interleukin-6 family of cytokines in inflammatory arthritis and bone turnover. Arthritis Rheum. 2003;48(5):

April 2005 Ark International Training Seminars IL-6 It is upregulated in type 1 diabetes, infections, inflammatory thyroid disease, RA, systemic sclerosis, psoriasis and various cancers. It is upregulated in type 1 diabetes, infections, inflammatory thyroid disease, RA, systemic sclerosis, psoriasis and various cancers. Major functions in neoplastic processes. Major functions in neoplastic processes. IL-6 may affect cancer progression by its actions on:-IL-6 may affect cancer progression by its actions on:- Cell adhesion and motilityCell adhesion and motility ThrombopoiesisThrombopoiesis Tumour specific antigen expressionTumour specific antigen expression Cancer cell proliferation.Cancer cell proliferation. Depending on the cell type, IL-6 can either inhibit or stimulate cancer cell proliferation. Depending on the cell type, IL-6 can either inhibit or stimulate cancer cell proliferation. Tumours stimulated by IL-6 include melanoma, renal cell carcinoma, prostate carcinoma, Kaposi's sarcoma, ovarian carcinoma, lymphoma and leukaemia, and multiple myeloma.Tumours stimulated by IL-6 include melanoma, renal cell carcinoma, prostate carcinoma, Kaposi's sarcoma, ovarian carcinoma, lymphoma and leukaemia, and multiple myeloma.

April 2005 Ark International Training Seminars IL-6 IL-6 levels are directly correlated with ageing in a variety of species, it may play an important role in the ageing process. IL-6 levels are directly correlated with ageing in a variety of species, it may play an important role in the ageing process. Intriguingly, dietary restriction, the only experimental intervention that reproducibly prolongs maximum lifespan in mammals can restore a variety of physiologic parameters, including IL-6 secretion and serum levels to the level in youth.Intriguingly, dietary restriction, the only experimental intervention that reproducibly prolongs maximum lifespan in mammals can restore a variety of physiologic parameters, including IL-6 secretion and serum levels to the level in youth. DHEA, currently thought to influence various ageing processes also has been shown to diminish the age-associated rise in serum IL- 6.DHEA, currently thought to influence various ageing processes also has been shown to diminish the age-associated rise in serum IL- 6.

April 2005 Ark International Training Seminars IL-6 an elevated IL-6 level is a strong and independent predictor of mortality for patients with acute coronary syndromes an elevated IL-6 level is a strong and independent predictor of mortality for patients with acute coronary syndromes Vorchheimer DA, Fuster V. Inflammatory markers in coronary artery disease. JAMA. 2001;286(17): Vorchheimer DA, Fuster V. Inflammatory markers in coronary artery disease. JAMA. 2001;286(17):

April 2005 Ark International Training Seminars IL-6 and hormonal function Glucocorticoids inhibit IL-6 expression. Glucocorticoids inhibit IL-6 expression. During times of stress or inflammation, IL-6 levels are increased.During times of stress or inflammation, IL-6 levels are increased. IL-6 can then induce release of corticotrophin-releasing factor, which results in elevated systemic levels of corticosteroids.IL-6 can then induce release of corticotrophin-releasing factor, which results in elevated systemic levels of corticosteroids. This provides a mechanism for a negative-feedback loop.This provides a mechanism for a negative-feedback loop.

April 2005 Ark International Training Seminars IL-6 Oestrogen inhibits IL-6 expression. Oestrogen inhibits IL-6 expression. Menopause or ovariectomy resulted in increased IL-6 serum levels and increased IL-6 secretion by mononuclear cells.Menopause or ovariectomy resulted in increased IL-6 serum levels and increased IL-6 secretion by mononuclear cells. Studies have also demonstrated that oestradiol inhibits bone marrow stromal cell and osteoblastic cell production.Studies have also demonstrated that oestradiol inhibits bone marrow stromal cell and osteoblastic cell production.

April 2005 Ark International Training Seminars IL-6 Important mediator of several infectious and autoimmune diseases. These include :- Important mediator of several infectious and autoimmune diseases. These include :- Rheumatoid arthritisRheumatoid arthritis Inflammatory joint disease, particularly rheumatoid arthritis, which is associated with, increased synovial fluid levels of IL-6.Inflammatory joint disease, particularly rheumatoid arthritis, which is associated with, increased synovial fluid levels of IL-6. SepsisSepsis Human immunodeficiency virus (HIV infection)Human immunodeficiency virus (HIV infection) Castleman's diseaseCastleman's disease Para-neoplastic symptoms associated with cardiac myxomaPara-neoplastic symptoms associated with cardiac myxoma

April 2005 Ark International Training Seminars

April 2005 Ark International Training Seminars IL-12 Generated from T and B-lymphocytes, NK cells and macrophages. Generated from T and B-lymphocytes, NK cells and macrophages. The production is of IL-12 is inhibited by IL-4 and IL-10. The production is of IL-12 is inhibited by IL-4 and IL-10. The stimulatory effect of IL-12 on TH1 development is antagonised by IL-4, a cytokine that promotes TH2 cell development.The stimulatory effect of IL-12 on TH1 development is antagonised by IL-4, a cytokine that promotes TH2 cell development. Proinflammatory cytokine. Proinflammatory cytokine. Excess production can indicate infection, inflammation, autoimmune disease and cancer Excess production can indicate infection, inflammation, autoimmune disease and cancer Found to be elevated in autism and MS Found to be elevated in autism and MS Enhances cytotoxic T cells Enhances cytotoxic T cells

April 2005 Ark International Training Seminars IL-13 Enhances the expression of MHC class 11 proteins (Major Histocompatability Complex) and thus antigen production. Enhances the expression of MHC class 11 proteins (Major Histocompatability Complex) and thus antigen production. MHC type 1 is always recognised by lymphocytes bearing cell surface protein CD8; MHC type 11 is always recognised by lymphocytes bearing CD4MHC type 1 is always recognised by lymphocytes bearing cell surface protein CD8; MHC type 11 is always recognised by lymphocytes bearing CD4 Increases CD23 expression. Increases CD23 expression. Causes the switching of antibody production to IgE and IgG4 Causes the switching of antibody production to IgE and IgG4 Brain tumour lines over-express a receptor for IL- 13 and these receptors block IL-4, whereas normal cells share receptors between IL-4 and IL-13 Brain tumour lines over-express a receptor for IL- 13 and these receptors block IL-4, whereas normal cells share receptors between IL-4 and IL-13 Low in the synovium of RA patients Low in the synovium of RA patients

April 2005 Ark International Training Seminars INTERFERONS Interferon is produced by T “helper” lymphocytes. There are two types of T cells: Interferon is produced by T “helper” lymphocytes. There are two types of T cells: Cytotoxic (or "killer") T cells, which aggressively screen other cells for signs of infection and malignancy and secrete toxic molecules to kill any aberrant cells;Cytotoxic (or "killer") T cells, which aggressively screen other cells for signs of infection and malignancy and secrete toxic molecules to kill any aberrant cells; "Helper" T cells, which cooperate with B cells (lymphocytes that mature in the bone marrow) in the antibody response to antigens such as bacterial toxins."Helper" T cells, which cooperate with B cells (lymphocytes that mature in the bone marrow) in the antibody response to antigens such as bacterial toxins. The helper T cells produce interferon and other cytokines in response to an antigen challenge. The helper T cells produce interferon and other cytokines in response to an antigen challenge. Before a B cell can produce and secrete antibodies, it must recognise a specific antigen and receive signals from certain cytokines. Before a B cell can produce and secrete antibodies, it must recognise a specific antigen and receive signals from certain cytokines.

April 2005 Ark International Training Seminars INTERFERONS Functions: Functions: Interferons fight infectious disease.Interferons fight infectious disease. They increase the phagocytic activity of macrophages.They increase the phagocytic activity of macrophages. Increase the cytotoxic activity of lymphocytes.Increase the cytotoxic activity of lymphocytes. Inhibits the replication of intracellular pathogens.Inhibits the replication of intracellular pathogens.

April 2005 Ark International Training Seminars IFN-  and IFN-  Both are generated by leukocytes and fibroblasts Both are generated by leukocytes and fibroblasts Their functions are : Their functions are : Antiviral properties.Antiviral properties. Interferon activates phagocytes.Interferon activates phagocytes. Anti-proliferative properties.Anti-proliferative properties. Interferon up-regulates MHC class I expressionInterferon up-regulates MHC class I expression Interferon -2 has been used to treat chronic myelogenous leukaemia and other myeloprolific disorders, perhaps by inhibiting oncogene expression.Interferon -2 has been used to treat chronic myelogenous leukaemia and other myeloprolific disorders, perhaps by inhibiting oncogene expression.

April 2005 Ark International Training Seminars IFN-  and IFN-  Used in combination with retinoids, interferon -2 has induced regression in advanced squamous carcinomas of the skin and cervix, suggesting that the cytokine may influence cell differentiation.Used in combination with retinoids, interferon -2 has induced regression in advanced squamous carcinomas of the skin and cervix, suggesting that the cytokine may influence cell differentiation. It also inhibits vascular and endothelial cell proliferation and thus has a place in treatment of melanomas, hypernephromas, and haemangiomas.It also inhibits vascular and endothelial cell proliferation and thus has a place in treatment of melanomas, hypernephromas, and haemangiomas. Because it can increase the intensity of antigen expression on certain tumours (ovarian and colorectal carcinomas), interferon -2 has potential for diagnostics (imaging) and therapeutics (monoclonal antibodies).Because it can increase the intensity of antigen expression on certain tumours (ovarian and colorectal carcinomas), interferon -2 has potential for diagnostics (imaging) and therapeutics (monoclonal antibodies).

April 2005 Ark International Training Seminars IFN-  IFN- is generated by T-lymphocytes and Natural Killer cells IFN- is generated by T-lymphocytes and Natural Killer cells Its functions are: Its functions are: Antiviral properties.Antiviral properties. The development of TH1 from TH0 cells and the inhibition of TH2 cells.The development of TH1 from TH0 cells and the inhibition of TH2 cells. It is the body’s most powerful macrophage-activating factor.It is the body’s most powerful macrophage-activating factor. Mediator of oxidative stress, stimulating macrophages to produce free radicals (used to kill cancer cells) Induction of apoptosis Increases the expression of both MHC type 1 and 11 proteins, thus enhancing antigen production.Increases the expression of both MHC type 1 and 11 proteins, thus enhancing antigen production. Stimulates the expression of VCAM.Stimulates the expression of VCAM. Stimulates the differentiation of cytotoxic T-cells.Stimulates the differentiation of cytotoxic T-cells. Inhibits IL-4.Inhibits IL-4. Promotes the synthesis of IgG2 by activated T cellsPromotes the synthesis of IgG2 by activated T cells over production of IFN- can be caused by toxins such as Epstein Barr virus

April 2005 Ark International Training Seminars IFN-  -inducing factor: (IGIF) It has been proposed that IGIF be designated as IL-18 It has been proposed that IGIF be designated as IL-18 Functions Functions Induces IFN- production more potently than IL-12Induces IFN- production more potently than IL-12 Induces the development of TH1 cells.Induces the development of TH1 cells. Enhances of NK cell cytotoxicityEnhances of NK cell cytotoxicity Augments GM-CSF productionAugments GM-CSF production Decreases IL-10 production.Decreases IL-10 production.

April 2005 Ark International Training Seminars TNF-  Generated by macrophages, mast cells and T-lymphocytes. Macrophages are stimulated to produce TNF by IFN- (i.e. TNF- is produced when IFN produces migration inhibition factor (MIF) when T -lymphocytes are stimulated by an endotoxin such as pathogenic bacteria or viral infections. Generated by macrophages, mast cells and T-lymphocytes. Macrophages are stimulated to produce TNF by IFN- (i.e. TNF- is produced when IFN produces migration inhibition factor (MIF) when T -lymphocytes are stimulated by an endotoxin such as pathogenic bacteria or viral infections. TNF-when in high concentrations as when it is induced by an endotoxin, can have the following effects: TNF-when in high concentrations as when it is induced by an endotoxin, can have the following effects: Pyrogenic properties; either directly via stimulation of PGE2 synthesis by the vascular endothelium of the hypothalamus, or indirectly by inducing the release of IL-1.Pyrogenic properties; either directly via stimulation of PGE2 synthesis by the vascular endothelium of the hypothalamus, or indirectly by inducing the release of IL-1. The production of acute phase proteins.The production of acute phase proteins. The stimulation of the production of nitric oxide.The stimulation of the production of nitric oxide. If TNF- is produced for long periods, then it produces cachexia.If TNF- is produced for long periods, then it produces cachexia. Destroys cells in the CNS that produce serotonin, leading to depressionDestroys cells in the CNS that produce serotonin, leading to depression

April 2005 Ark International Training Seminars TNF-  TNF- and diet TNF- and diet High levels of carbohydrates or fats increases activity of TNFHigh levels of carbohydrates or fats increases activity of TNF High levels of protein does not increase activity of TNF-.High levels of protein does not increase activity of TNF-. TNF- when produced in low concentrations: TNF- when produced in low concentrations: Up-regulates the inflammatory response.Up-regulates the inflammatory response. Induces expression of ICAM-1, VCAM-1 and E- selectin.Induces expression of ICAM-1, VCAM-1 and E- selectin. Enhances killing of intracellular organisms such as Leishmania and Mycobacterium tuberculosis.Enhances killing of intracellular organisms such as Leishmania and Mycobacterium tuberculosis. Activates leukocytes to produce IL-6 and TNF- itself.Activates leukocytes to produce IL-6 and TNF- itself. Levels are raised in vitamin B12 deficiency (with EGF) causing alteration in Th1 & Th2 balance Levels are raised in vitamin B12 deficiency (with EGF) causing alteration in Th1 & Th2 balance

April 2005 Ark International Training Seminars TNF-  TNF-b is produced by activated T-cells TNF-b is produced by activated T-cells Its properties are similar to those of TNF- and include: Its properties are similar to those of TNF- and include: The induction of apoptosis (programmed cell death) in many types of transformed, virally infected, and tumour cells.The induction of apoptosis (programmed cell death) in many types of transformed, virally infected, and tumour cells. The stimulation of several PMN (polymorphonuclear leukocytes) effector functions.The stimulation of several PMN (polymorphonuclear leukocytes) effector functions. TNF- lyses tumour cells.TNF- lyses tumour cells. TNF- activates neutrophils.TNF- activates neutrophils. TNF- increases the adhesion of leukocytes to the vascular endothelium.TNF- increases the adhesion of leukocytes to the vascular endothelium. Found in excess in MS, RA, infection and type 1 diabetes Found in excess in MS, RA, infection and type 1 diabetes

April 2005 Ark International Training Seminars Transforming growth factor-ß: (TGF-ß) Family of cytokines that includes five isoforms; Family of cytokines that includes five isoforms; TGF-ß1, ß2, and ß3 that are from separate genes yet, bind to the same high affinity receptor.TGF-ß1, ß2, and ß3 that are from separate genes yet, bind to the same high affinity receptor. TGFs are trophic polypeptides that stimulate the proliferation and differentiation of different cell types of mesenchymal origin TGFs are trophic polypeptides that stimulate the proliferation and differentiation of different cell types of mesenchymal origin Derived from T cells, platelets, and monocytes.: Derived from T cells, platelets, and monocytes.: Inhibits T cell and NK cell proliferation and activation. Inhibits T cell and NK cell proliferation and activation.

April 2005 Ark International Training Seminars Transforming growth factor-ß: (TGF-ß) At a site of injury, At a site of injury, TGF-ß (stored in platelets) will be released upon the degranulation of mast cells.TGF-ß (stored in platelets) will be released upon the degranulation of mast cells. TGF-ß then attracts monocytes and other leukocytes to the site, thus participating in the initial step of chronic inflammation.TGF-ß then attracts monocytes and other leukocytes to the site, thus participating in the initial step of chronic inflammation. TGF-ß then positively regulates its own production and the production and deposition of extracellular matrix components as well as the expression of integrins resulting in enhanced cell adhesion.TGF-ß then positively regulates its own production and the production and deposition of extracellular matrix components as well as the expression of integrins resulting in enhanced cell adhesion. Up-regulates IL-1, fibroblast growth factor (FGF), platelet-derived growth factor (PDGF) and TNF-. Up-regulates IL-1, fibroblast growth factor (FGF), platelet-derived growth factor (PDGF) and TNF-.

April 2005 Ark International Training Seminars Anti-inflammatory or suppressing cytokines IL-4, IL-4, IL-5, IL-5, IL-10, IL-10, IL-13 IL-13

April 2005 Ark International Training Seminars IL-4 Mainly derived from Th2 cells (CD4 cells), mast cells and basophils Mainly derived from Th2 cells (CD4 cells), mast cells and basophils It is a structural homologue of IL-13It is a structural homologue of IL-13 Suppresses the production of pro-inflammatory cytokines Suppresses the production of pro-inflammatory cytokines Suppresses the production of TNF-a, IL-1, IL-6 & IL-8Suppresses the production of TNF-a, IL-1, IL-6 & IL-8 Involved in the development of Th2 subsetInvolved in the development of Th2 subset Involved in B-lymphocyte productionInvolved in B-lymphocyte production Initiates growth of mast cellsInitiates growth of mast cells Stimulates synthesis of extracellular matrix Stimulates synthesis of extracellular matrix Cause the switching of antibody production to IgE and IgG Cause the switching of antibody production to IgE and IgG

April 2005 Ark International Training Seminars IL-4 Responsible for the induction of CD8 Responsible for the induction of CD8 Stimulates production of VCAM-1 Stimulates production of VCAM-1 Enhances expression of MHC class 11 proteins and thus antigen production Enhances expression of MHC class 11 proteins and thus antigen production Anti-inflammatory action in synovial membranes by inhibiting the pro- inflammatory cytokines IL-1, Il-6, IL-8 and TNF- Anti-inflammatory action in synovial membranes by inhibiting the pro- inflammatory cytokines IL-1, Il-6, IL-8 and TNF- Its actions are antagonised by IFN- and vice versa. Its actions are antagonised by IFN- and vice versa. It is a synergist with IL-3 It is a synergist with IL-3 Low in the synovium of RA patients Low in the synovium of RA patients

April 2005 Ark International Training Seminars IL-5 Derived from Th2 cells (CD4 T helper cells) and activated mast cells like IL-4. Derived from Th2 cells (CD4 T helper cells) and activated mast cells like IL-4. Stimulates growth of eosinophils, Stimulates growth of eosinophils, which are responsible for killing the helminth family of parasiteswhich are responsible for killing the helminth family of parasites Stimulates the growth and differentiation of B- cells Stimulates the growth and differentiation of B- cells It induces the synthesis of IgA and IgM in mature B-lymphocytes It induces the synthesis of IgA and IgM in mature B-lymphocytes Enhancement of T cell cytotoxicity Enhancement of T cell cytotoxicity High levels are associated with asthma and atopy High levels are associated with asthma and atopy

April 2005 Ark International Training Seminars IL-5 Derived from Th2 cells (CD4 T helper cells) and activated mast cells like IL-4. Derived from Th2 cells (CD4 T helper cells) and activated mast cells like IL-4. Stimulates growth of eosinophils, Stimulates growth of eosinophils, which are responsible for killing the helminth family of parasiteswhich are responsible for killing the helminth family of parasites Stimulates the growth and differentiation of B- cells Stimulates the growth and differentiation of B- cells It induces the synthesis of IgA and IgM in mature B-lymphocytes It induces the synthesis of IgA and IgM in mature B-lymphocytes Enhancement of T cell cytotoxicity Enhancement of T cell cytotoxicity High levels are associated with asthma and atopy High levels are associated with asthma and atopy

April 2005 Ark International Training Seminars IL-10 Generated from CD4 T cells, activated CD8+ T lymphocytes, B-lymphocytes, macrophages, activated mast cells and epidermal cells. Generated from CD4 T cells, activated CD8+ T lymphocytes, B-lymphocytes, macrophages, activated mast cells and epidermal cells. It is an anti-inflammatory cytokine along with IL- 4 and IL-13. It is an anti-inflammatory cytokine along with IL- 4 and IL-13. Down-regulates the macrophage production of IL-1, IFN- and TNF-.Down-regulates the macrophage production of IL-1, IFN- and TNF-. Inhibits the production of IL-2 induced IFN- by NK cells.Inhibits the production of IL-2 induced IFN- by NK cells. Promotes the inhibition of IL-4 and IFN- induced MHC class II expression on monocytes.Promotes the inhibition of IL-4 and IFN- induced MHC class II expression on monocytes. It is over-expressed in some viral, bacterial and parasitic infections It is over-expressed in some viral, bacterial and parasitic infections

April 2005 Ark International Training Seminars IL-10 Inhibits nitric oxide production. Inhibits nitric oxide production. Stimulates B-cell proliferation. Stimulates B-cell proliferation. Inhibits macrophage/monocyte activation. Inhibits macrophage/monocyte activation. Suppresses activity of peripheral blood lymphocytes (important in graft rejection). Suppresses activity of peripheral blood lymphocytes (important in graft rejection). High in the synovial fluid of RA patients, but not enough to suppress the pro-inflammatory response in RA High in the synovial fluid of RA patients, but not enough to suppress the pro-inflammatory response in RA

April 2005 Ark International Training Seminars Inducible cytokines These cytokines have differing responses in different environments and influences These cytokines have differing responses in different environments and influences

April 2005 Ark International Training Seminars IL-3 Generated from activated T-cells and mast cells. Generated from activated T-cells and mast cells. Stimulates eosinophils and B cell differentiation. Stimulates eosinophils and B cell differentiation. Inhibits lymphokine-activated killer (LAK) cell activity. Inhibits lymphokine-activated killer (LAK) cell activity. Shares several biological activities with GM-CSF. Shares several biological activities with GM-CSF. Supports the survival of cholinergic neurones. Supports the survival of cholinergic neurones. Stimulates production of proteoglycans Stimulates production of proteoglycans

April 2005 Ark International Training Seminars IL-7 Derived from stromal cells in bone marrow and thymus. Derived from stromal cells in bone marrow and thymus. Stimulates proliferation of B-cell progenitors Stimulates proliferation of B-cell progenitors Stimulates mature T-cells Stimulates mature T-cells Enhances cytotoxicity Enhances cytotoxicity

April 2005 Ark International Training Seminars IL-8 Derived from phagocytes, antigen-activated T cells, endothelial and epithelial cells, and even neutrophils. Derived from phagocytes, antigen-activated T cells, endothelial and epithelial cells, and even neutrophils. Controls cell migration to inflammatory sites Controls cell migration to inflammatory sites By activating the chemotactic migration and activation of neutrophils and other cell types (such as monocytes, lymphocytes, basophils, and eosinophils) at sites of inflammation.By activating the chemotactic migration and activation of neutrophils and other cell types (such as monocytes, lymphocytes, basophils, and eosinophils) at sites of inflammation. Stimulate granulocyte activity Stimulate granulocyte activity Up-regulates cell-surface adhesion molecule expression Up-regulates cell-surface adhesion molecule expression ↑ endothelial leukocyte adhesion molecule (ELAM-1) ↑ endothelial leukocyte adhesion molecule (ELAM-1) ↑ intracellular adhesion molecule, ICAM-1 ↑ intracellular adhesion molecule, ICAM-1 Hence enhancing neutrophil adherence to endothelial cells and facilitating their diapedesis through vessel walls. Hence enhancing neutrophil adherence to endothelial cells and facilitating their diapedesis through vessel walls.

April 2005 Ark International Training Seminars IL-9 Generated from CD4 T helper cells and some B lymphomas. Generated from CD4 T helper cells and some B lymphomas. Dependent on IL-4, IL-10 and IL-2. Dependent on IL-4, IL-10 and IL-2. Promotes proliferation of T-cells – CH8 T cells. Promotes proliferation of T-cells – CH8 T cells. It inhibits lymphokine production by IFN-- producing CD4+ T cells. It inhibits lymphokine production by IFN-- producing CD4+ T cells. Increase production of immunoglobulins and proliferation of mast cells. Increase production of immunoglobulins and proliferation of mast cells.

April 2005 Ark International Training Seminars IL-11 Generated from bone stromal cells and some fibroblasts. Generated from bone stromal cells and some fibroblasts. Functional homologue of IL-6 and can replace IL- 6 in the induction of acute phase proteins in the liver. Functional homologue of IL-6 and can replace IL- 6 in the induction of acute phase proteins in the liver. Produces acute phase proteins in the liver.Produces acute phase proteins in the liver. Induces IL-6 expression by CD4+ T cells.Induces IL-6 expression by CD4+ T cells. Promotes lymphopoiesis. Promotes lymphopoiesis. Promotes the growth of haemopoietic cells. Promotes the growth of haemopoietic cells. Stimulates T cell-dependent B cell immunoglobulin secretion, Stimulates T cell-dependent B cell immunoglobulin secretion, Stimulates platelet production. Stimulates platelet production.

April 2005 Ark International Training Seminars IL-14 Generated from T-lymphocyte and malignant B-lymphocytes. Generated from T-lymphocyte and malignant B-lymphocytes. Induces proliferation of activated B- cells Induces proliferation of activated B- cells Inhibits immunoglobulin production Inhibits immunoglobulin production It has been suggested that IL-14 plays an important role in an aggressive form of B-cell type non- Hodgkin’s lymphoma It has been suggested that IL-14 plays an important role in an aggressive form of B-cell type non- Hodgkin’s lymphoma

April 2005 Ark International Training Seminars IL-15 The human IL-15 gene has been mapped to chromosome 4, similarly to IL-2. The human IL-15 gene has been mapped to chromosome 4, similarly to IL-2. Generated from epithelial cells, activated monocytes and fibroblasts. Generated from epithelial cells, activated monocytes and fibroblasts. Shares many biologic properties with IL-2 and mediates its activity via a high affinity receptor comprised of a unique alpha chain (to IL-15) and the beta and gamma chains of the IL-2. Shares many biologic properties with IL-2 and mediates its activity via a high affinity receptor comprised of a unique alpha chain (to IL-15) and the beta and gamma chains of the IL-2.

April 2005 Ark International Training Seminars IL-15 Stimulates T-cell production by binding to IL-2 receptor sites Stimulates T-cell production by binding to IL-2 receptor sites Stimulates NK cell proliferation, as well as CTL and LAK activity. Stimulates NK cell proliferation, as well as CTL and LAK activity. Enhances B cell expansion and immunoglobulin production. Enhances B cell expansion and immunoglobulin production. It functions also a T lymphocyte chemo- attractant. It functions also a T lymphocyte chemo- attractant. IL-15 may be responsible for the recruitment and activation of T lymphocytes in the synovium of patients with rheumatoid arthritis where its levels have been found to be elevated IL-15 may be responsible for the recruitment and activation of T lymphocytes in the synovium of patients with rheumatoid arthritis where its levels have been found to be elevated

April 2005 Ark International Training Seminars IL-16: The only member of the "C" family of chemokines. The only member of the "C" family of chemokines. It is an unusual cytokine in that pre- formed IL-16 is stored in CD8+ lymphocytes and is secreted upon stimulation with histamine or serotonin. It is an unusual cytokine in that pre- formed IL-16 is stored in CD8+ lymphocytes and is secreted upon stimulation with histamine or serotonin. It induces chemotaxis of CD4+ T lymphocytes. It induces chemotaxis of CD4+ T lymphocytes. Initiates T cell mediated inflammation in asthma. Initiates T cell mediated inflammation in asthma.

April 2005 Ark International Training Seminars IL-17: Generated from activated T lymphocytes. Generated from activated T lymphocytes. Stimulates IL-6 and IL-8 production. Stimulates IL-6 and IL-8 production. Enhances ICAM-1 expression Enhances ICAM-1 expression Excess in synovium of RA patients. Excess in synovium of RA patients.

April 2005 Ark International Training Seminars Colony stimulating factors: (G-CSF and GM-CSF) There are two forms of Colony Stimulating Factors: There are two forms of Colony Stimulating Factors: Granulocyte-Colony Stimulating Factor G-CSF).Granulocyte-Colony Stimulating Factor G-CSF). Granulocyte macrophage-CSF (GM-CSF).Granulocyte macrophage-CSF (GM-CSF). They are derived from monocytes, T lymphocytes, fibroblasts and endothelial cells that are activated by macrophage products such as the pro-inflammatory cytokines IL-1 and TNF. They are derived from monocytes, T lymphocytes, fibroblasts and endothelial cells that are activated by macrophage products such as the pro-inflammatory cytokines IL-1 and TNF. They both participate in acute inflammation. They both participate in acute inflammation. They both can stimulate neutrophils. They both can stimulate neutrophils. GM-CSF can also activate effector functions of eosinophils and mononuclear phagocytes. GM-CSF can also activate effector functions of eosinophils and mononuclear phagocytes.

April 2005 Ark International Training Seminars Epidermal growth factor Trophic polypeptides that stimulates the proliferation and differentiation of different cell types. Trophic polypeptides that stimulates the proliferation and differentiation of different cell types. Potent stimulator of astrocyte proliferation. Potent stimulator of astrocyte proliferation. EGF is not synthesized by the developing neuronal cells, (but its homologue, TGF-, is expressed in the brain.) EGF is not synthesized by the developing neuronal cells, (but its homologue, TGF-, is expressed in the brain.) During gliogenesis, EGF is detected in tissues and in the blood. During gliogenesis, EGF is detected in tissues and in the blood. EGF is known to strongly affect the morphology of astrocytes and induce upregulation of the glutamine. EGF is known to strongly affect the morphology of astrocytes and induce upregulation of the glutamine. In the peripheral nervous system (PNS) studies have indicated that individual growth factors act as critical determinants of transmitter type.In the peripheral nervous system (PNS) studies have indicated that individual growth factors act as critical determinants of transmitter type. In the brain, however, the initiation of neurotransmitter specific genes appears to involve more complex mechanisms, requiring the obligatory interaction of multiple signal moleculesIn the brain, however, the initiation of neurotransmitter specific genes appears to involve more complex mechanisms, requiring the obligatory interaction of multiple signal molecules

April 2005 Ark International Training Seminars Fibroblast growth factors (FGFs) The family of fibroblast growth factors (FGFs) include several forms The family of fibroblast growth factors (FGFs) include several forms They occur in many peripheral tissues. They occur in many peripheral tissues. The brain and pituitary are rich sources of FGF-The brain and pituitary are rich sources of FGF- They are potent mitogens for a large number of cell types.. They are potent mitogens for a large number of cell types..

April 2005 Ark International Training Seminars GM-CSF & asthma In asthma’s airway inflammation, In asthma’s airway inflammation, GM-CSF, IL-3 and IL-5 perpetuate the eosinophil activation and their survival.GM-CSF, IL-3 and IL-5 perpetuate the eosinophil activation and their survival. Probably derived from alveolar macrophages (2-3 times the level of control macrophages) or the T-lymphocytes present in the airways Probably derived from alveolar macrophages (2-3 times the level of control macrophages) or the T-lymphocytes present in the airways IL-4 and IL-13 (stimulatory) and IFN- (inhibitory) control IgE synthesisIL-4 and IL-13 (stimulatory) and IFN- (inhibitory) control IgE synthesis IL-1 and TNF- up-regulation the expression of the endothelial adhesion molecule.IL-1 and TNF- up-regulation the expression of the endothelial adhesion molecule.

April 2005 Ark International Training Seminars Hormone regulation Hormone regulation: Hormone regulation: Upstream to the pituitary (stimulating hormones) and hypothalamus (regulating hormonesUpstream to the pituitary (stimulating hormones) and hypothalamus (regulating hormones Downstream via metabolic pathways in relationship to the cofactors in their synthesisDownstream via metabolic pathways in relationship to the cofactors in their synthesis Downstream via liver and other cellular detoxification pathwaysDownstream via liver and other cellular detoxification pathways

April 2005 Ark International Training Seminars Hormonal Immune reciprocity The sympathetic nervous system (SNS) The parasympathetic nervous system (PNS) The hypothalamus-pituitary-adrenal cortex axis The hypothalamus – pituitary-thymus axis The hypothalamus-pituitary-thyroid axis

April 2005 Ark International Training Seminars HPA axis (hypothalamic-pituitary- adrenal) Adrenal – gonadal hormones Adrenal – gonadal hormones Oestrogen 18- carbon chainOestrogen 18- carbon chain Androgens 19 carbon chainAndrogens 19 carbon chain Progesterone 21 carbon chainProgesterone 21 carbon chain The balance the glucocorticosteroid hormones (21 carbon chain) is important in regulating the inflammatory response The balance the glucocorticosteroid hormones (21 carbon chain) is important in regulating the inflammatory response

April 2005 Ark International Training Seminars Female HPA axis Testosterone does not have a direct feedback to the pituitary

April 2005 Ark International Training Seminars Male HPA axis Testosterone does have a direct feedback to the pituitary

April 2005 Ark International Training Seminars HPA axis HPA axis (hypothalamic-pituitary-adrenal) HPA axis (hypothalamic-pituitary-adrenal) Corticotrophin releasing hormone (CRH)Corticotrophin releasing hormone (CRH) Anti-inflammatory Anti-inflammatory The major stress response mediator of the CNS The major stress response mediator of the CNS Immunosuppressive centrally under sympathetic stimulation Immunosuppressive centrally under sympathetic stimulation Stimulated by oestrogen Stimulated by oestrogen ACTHACTH Responsible for cortisol production Responsible for cortisol production Anti-inflammatory Anti-inflammatory Immunosuppressive Immunosuppressive Hence capable of relieving symptoms of RAHence capable of relieving symptoms of RA Gonadal androgensGonadal androgens Inhibit IL-6, TNF-, IL-1 production Inhibit IL-6, TNF-, IL-1 production

April 2005 Ark International Training Seminars HPA axis HPA axis HPA axis Melanocyte stimulating hormone (MSH)Melanocyte stimulating hormone (MSH) Cytokine antagonist inhibiting: Cytokine antagonist inhibiting: IL-1IL-1 IL-6IL-6 TNF-TNF- INF-INF- TSHTSH Increases IL-2 Increases IL-2 ↑ immunoglobulin secretion by activating B- cells ↑ immunoglobulin secretion by activating B- cells

April 2005 Ark International Training Seminars HPA axis DHEADHEA Enhances IL-2 & INF- production Enhances IL-2 & INF- production Enhance Th1 response Enhance Th1 response OestrogensOestrogens Enhance Th1 & Th2 activity Enhance Th1 & Th2 activity ProlactinProlactin Potent pro-inflammatory effects Potent pro-inflammatory effects Prolactin levels correlate with the severity of the disease, not the number of swollen joints Prolactin levels correlate with the severity of the disease, not the number of swollen joints Lymphocyte derived prolactin may be the reason that cabergoline does not reduce CRP and ESR Lymphocyte derived prolactin may be the reason that cabergoline does not reduce CRP and ESR

April 2005 Ark International Training Seminars HPA axis Defective Neuroendocrine communication (NEI) characterised by abnormal response of cortisol, prolactin, vasopressin, and - endorphin to certain stimuli in RA. Defective Neuroendocrine communication (NEI) characterised by abnormal response of cortisol, prolactin, vasopressin, and - endorphin to certain stimuli in RA. Adrenal and gonadal deficiencies thought to facilitate T cell dependent diseases (RA)- a predominantly pro-inflammatory terrainAdrenal and gonadal deficiencies thought to facilitate T cell dependent diseases (RA)- a predominantly pro-inflammatory terrain Low testosterone & dihydrotestosterone, low DHEALow testosterone & dihydrotestosterone, low DHEA Excess prolactin exaggerates RAExcess prolactin exaggerates RA These are not a response to inflammation but pre-exist the diseaseThese are not a response to inflammation but pre-exist the disease High oestrogen thought to facilitate B cell dependent immune complex diseases (Lupus) High oestrogen thought to facilitate B cell dependent immune complex diseases (Lupus)

April 2005 Ark International Training Seminars Effect of oestrogen on immune system Cells Thymocytes Thymocytes Lymphocytes Lymphocytes CD8 T-cellsCD8 T-cells CD4 T-cellsCD4 T-cells B-cellsB-cells Macrophages Macrophages Cytokine productionCytokine production Proto-oncogene productionProto-oncogene production HLA expressionHLA expression Endothelial cells Endothelial cells Adhesion moleculesAdhesion molecules Adhesion of peripheral mononuclear cells to endotheliumAdhesion of peripheral mononuclear cells to endothelium Cell apoptosis Cell apoptosis Physiological levels Pharmacological levels ↑ ? ↑ ↓↓ ↑ ↓ ↑↑↑↑ ↑↑↓ ↑ ? ↑↓ ↑ ? ↑↓ ↓ ?

April 2005 Ark International Training Seminars Effect of androgens on immune system Cells Thymocytes Thymocytes Lymphocytes Lymphocytes CD8 T-cellsCD8 T-cells Macrophages Macrophages Cytokine productionCytokine production Proto-oncogene productionProto-oncogene production HLA expressionHLA expression Chondrocytes Chondrocytes DNA synthesisDNA synthesis Proteoglycan synthesisProteoglycan synthesis Cell apoptosis Cell apoptosis Reduced synthesis of IL-2 Reduced synthesis of IL-2 ? ↑ ? ↑ Inhibition synthesis IL-1 Inhibition synthesis IL-1 ? ↓ ↑ ↑ ? ↑ ? ↑

April 2005 Ark International Training Seminars Sex hormones and inflammatory process

April 2005 Ark International Training Seminars Low oestrogen and inflammation Low oestrogen: Low oestrogen: MenopauseMenopause SurgerySurgery Increase in pro-inflammatory cytokines Increase in pro-inflammatory cytokines Supplementation of oestradiol inhibits IL-1 and TNF- and possibly inhibits IL-6 Supplementation of oestradiol inhibits IL-1 and TNF- and possibly inhibits IL-6 Cytokines modulated by oestrogen: Cytokines modulated by oestrogen: IL-1, IL-6, TNF-, M-CSF, GM-CSF, TGF- IL-1, IL-6, TNF-, M-CSF, GM-CSF, TGF- 

April 2005 Ark International Training Seminars Macrophage and T-cell pathways in RA

April 2005 Ark International Training Seminars Peptidergic nerve regulation Pro-inflammatory Pro-inflammatory Substance PSubstance P Potentiates angiogenesis Potentiates angiogenesis Calcitonin gene related peptideCalcitonin gene related peptide Anti-inflammatory Anti-inflammatory SomatostatinSomatostatin

April 2005 Ark International Training Seminars Hormones and immune system Neuropeptides Bone marrow ThymusAntibody Cell mediated immunity Inflammation ACTH↓↓↓ Vasopressin↑ CRH↓↓↓↓  -endorphin ↕↕↕ Enkephalin↕↕↕ Insulin↑↑ MSH↓↓↓ LH↑ Somatostatin↓ IgA↕ Substance P ↕↑ Vasoactive Intestinal peptide ↓ IL-2 ↓ IL-4 ↕ IgA ↕

April 2005 Ark International Training Seminars HormoneIL-1TNF-aIL-6 INF-  IL-2 ACTH ↑↑↓ CRH ↕↕↓↕ B-endorphin ↑↕ Encephalin ↑↑↑ FSH ↑↑ Growth hormone ↑↑↑↑ Insulin ↑↑ Luteinising hormone ↑↑ MSH ↓↓↓ Prolactin ↑ Somatostatin ↓ Substance P ↑↑↑↑ Thyrotropin releasing hormone ↑ TSH ↓

April 2005 Ark International Training Seminars HPA : HPT axis

April 2005 Ark International Training Seminars General pattern of stress response Increased noradrenalin Increased dopamine Decreased serotonin Sympathetic dominance (adrenergic component). Loss of parasympathetic tone Decrease in hypothalamus-pituitary-adrenal cortex axis activity Decreased in hypothalamus-pituitary-thymus axis activity Decrease in secretion of growth hormone, prolactin and androgens Increase in ACTH, CRH, cortisol, oestrogens and somatostatin Increased Th2 immune activity

April 2005 Ark International Training Seminars Hypoactivity of HPA axis Fatigue Fatigue Inflammation Inflammation Autoimmune disease Autoimmune disease Myocardial infarction Myocardial infarction Apathy Apathy Anorexia Anorexia Weight loss Weight loss Insomnia Insomnia Weakness Weakness Loss of libido Loss of libido Pain Pain Asthma Asthma Allergies Allergies Loss of mental concentration Loss of mental concentration

April 2005 Ark International Training Seminars Hyperactivity of the HPA axis Anxiety Anxiety Agitation Agitation Insomnia Insomnia Hypercholesterolaemia Hypercholesterolaemia Increased triglycerides Increased triglycerides Fatigue Fatigue Depression Depression Hypertension Hypertension GI tract disorders GI tract disorders Central obesity Central obesity Loss of muscle tone Loss of muscle tone Osteoporosis Osteoporosis Loss immune function Loss immune function Poor recovery from illness or injury Poor recovery from illness or injury Infertility Infertility Reduced kidney function Reduced kidney function

April 2005 Ark International Training Seminars

April 2005 Ark International Training Seminars Inflammation and the Gut Gut bacteria (2½ to 3 pounds weight) Gut bacteria (2½ to 3 pounds weight) the second largest organ by mass in your body, second only to the muscles.the second largest organ by mass in your body, second only to the muscles. bacteria are connected to the rest of the body by the lymphatic system and the hepato-portal blood supply.bacteria are connected to the rest of the body by the lymphatic system and the hepato-portal blood supply. Any abnormal message is communicated from the gut bacteria to the receptor sites on the mucosal lining of the gut will modify the pro and anti-inflammatory balance. Any abnormal message is communicated from the gut bacteria to the receptor sites on the mucosal lining of the gut will modify the pro and anti-inflammatory balance. IL-10 decreased IL-10 decreased IL-10 is an anti-inflammatory cytokineIL-10 is an anti-inflammatory cytokine TNF a and IL-1b increased. TNF a and IL-1b increased. TNF-a and the IL-1b are proinflammatory cytokines.TNF-a and the IL-1b are proinflammatory cytokines.

April 2005 Ark International Training Seminars CONTROLLED TURNOVER OF THE EXTRACELLULAR MATRIX Cytokine and cell proliferation factor influence on matrix: Cytokine and cell proliferation factor influence on matrix: IL-1, prostaglandin E2, PDGF, EGF all stimulate inflammation in low tissue pH (acidosis) and HA synthesisIL-1, prostaglandin E2, PDGF, EGF all stimulate inflammation in low tissue pH (acidosis) and HA synthesis Proteases break down the GAGs into HA fragments that bind too much water causing oedema and increased pressureProteases break down the GAGs into HA fragments that bind too much water causing oedema and increased pressure This is the case in acute inflammatory joint diseaseThis is the case in acute inflammatory joint disease This can be the result of trauma, abnormal usage or infectionThis can be the result of trauma, abnormal usage or infection

April 2005 Ark International Training Seminars P H AND THE EXTRACELLULAR MATRIX In abnormal pH, (acidic environment) the matrix regulation is disturbed and fibroblast, macrophages and neutrophils will release proteolytic enzymes that breakdown the GAGs of the extracellular matrix. In abnormal pH, (acidic environment) the matrix regulation is disturbed and fibroblast, macrophages and neutrophils will release proteolytic enzymes that breakdown the GAGs of the extracellular matrix. The fragments are then removed by macrophages. The fragments are then removed by macrophages.

April 2005 Ark International Training Seminars P H AND THE MATRIX This effects cellular metabolism by increasing the percentage of anaerobic respiration hence increasing the production of lactic acid and therefore further increasing the acidity. This effects cellular metabolism by increasing the percentage of anaerobic respiration hence increasing the production of lactic acid and therefore further increasing the acidity. Since the extracellular matrix acts as a store of toxins, acidity prevents toxins from being removed into the matrix and hence preventing cell damage. Since the extracellular matrix acts as a store of toxins, acidity prevents toxins from being removed into the matrix and hence preventing cell damage. The matrix stores toxins in an alkaline state and eliminates them in the acidic state. The matrix stores toxins in an alkaline state and eliminates them in the acidic state.

April 2005 Ark International Training Seminars P H AND THE MATRIX This abnormal pH is evidence of a disruption in the gut where the normal fluctuation (circadian rhythm) of the extracellular matrix pH from acidic to alkaline state between meals has become defective, leaving a permanent acidic state. The acidity induces a loss of motion in the matrix as the proteoglycans become more rigid. This abnormal pH is evidence of a disruption in the gut where the normal fluctuation (circadian rhythm) of the extracellular matrix pH from acidic to alkaline state between meals has become defective, leaving a permanent acidic state. The acidity induces a loss of motion in the matrix as the proteoglycans become more rigid.

April 2005 Ark International Training Seminars OXIDATIVE STRESS AND THE MATRIX In the presence of increased oxidative stress in the extracellular matrix, the free radicals can cause non-enzymatic breakdown of the GAGs. This can be a major factor in the developmental pathology of certain chronic conditions and cancer In the presence of increased oxidative stress in the extracellular matrix, the free radicals can cause non-enzymatic breakdown of the GAGs. This can be a major factor in the developmental pathology of certain chronic conditions and cancer

April 2005 Ark International Training Seminars STRESS RESPONSE AND THE MATRIX Chronic inflammation induces a state where small short acting stimuli produce an exaggerated long term reaction in the matrix and even more structural changes and loss of regulation. These changes in the matrix are not just material, they modify the resonance and oscillation patterns of the tissues in question and contribute to their losing phase coherence with the rest of the body (cf encapsulation in Traditional Chinese Medicine). Chronic inflammation induces a state where small short acting stimuli produce an exaggerated long term reaction in the matrix and even more structural changes and loss of regulation. These changes in the matrix are not just material, they modify the resonance and oscillation patterns of the tissues in question and contribute to their losing phase coherence with the rest of the body (cf encapsulation in Traditional Chinese Medicine).

April 2005 Ark International Training Seminars Chronic disease In chronic disease, it becomes essential to: treat the problem that is initiating the symptoms, provide therapy to get back regulation capacity in the extracellular matrix initiate Dynamic Stillness in the tissues regulate matrix pH restore mitochondrial function clear toxic metal, chemical and other biological toxins restore cytokine and other cell communication factor balance improve life style diet and exercise find the chronic hidden focuses of infection that are causing the dysregulation of the matrix.

April 2005 Ark International Training Seminars Homeopathy: Inflammation Neuroendocrine axis Neuroendocrine axis Ovarium compositum and Tonsilla compositumOvarium compositum and Tonsilla compositum Glandula suprarenalis suis-Injeel, Hypothalamus suis-Injeel and Funiculus umbilicalis suis-InjeelGlandula suprarenalis suis-Injeel, Hypothalamus suis-Injeel and Funiculus umbilicalis suis-Injeel CNS imbalance CNS imbalance Thalamus compositumThalamus compositum Sleep disturbance Sleep disturbance Altered pain threshold Altered pain threshold

April 2005 Ark International Training Seminars Homeopathy: Fibromyalgia Connective tissue disorder Connective tissue disorder Detox HomeopathicsDetox Homeopathics Thyroidea compositumThyroidea compositum Increase metabolism of the matrix Increase metabolism of the matrix Pulsatilla compositumPulsatilla compositum Increase metabolism of the matrix Increase metabolism of the matrix Ubichinon compositumUbichinon compositum Rebalance matrix pH and toxicity Rebalance matrix pH and toxicity

April 2005 Ark International Training Seminars

April 2005 Ark International Training Seminars Homeopathy: PATHOGENS CELLULAR ECOLOGY. CELLULAR ECOLOGY. The primitive life of symbiotic organisms live in a strong alkaline pH,The primitive life of symbiotic organisms live in a strong alkaline pH, bacterial life forms live in a mild alkaline pH,bacterial life forms live in a mild alkaline pH, fungal life forms live in a medium acidic pHfungal life forms live in a medium acidic pH viral life forms live in a strong acidic pH.viral life forms live in a strong acidic pH.

April 2005 Ark International Training Seminars Homeopathy: PATHOGENS In order to keep the right environment, every microbe produces an organic acid: Mucor racemosus -- lactic acid, Aspergillus niger -- citric acid. In order to keep the right environment, every microbe produces an organic acid: Mucor racemosus -- lactic acid, Aspergillus niger -- citric acid. These two primitive life forms that we all have, Mucor racemosus and aspergillus niger produce the lactic acid and citric acid respectively needed to maintain the “terrain” in a healthy alkaline form. These two primitive life forms that we all have, Mucor racemosus and aspergillus niger produce the lactic acid and citric acid respectively needed to maintain the “terrain” in a healthy alkaline form.

April 2005 Ark International Training Seminars Further studies Overview of homeopathic practice within a kinesiology framework: Overview of homeopathic practice within a kinesiology framework: July 7 th -9 th RIBA, LondonJuly 7 th -9 th RIBA, London Key toxinsKey toxins Pathogenic life formsPathogenic life forms Balance of pH environmentBalance of pH environment Drainage remediesDrainage remedies Enderlein remediesEnderlein remedies

April 2005 Ark International Training Seminars Further studies Allergy and Toxicity Course: Allergy and Toxicity Course: September 21 st -24 th RIBA, LondonSeptember 21 st -24 th RIBA, London DetoxificationDetoxification Key toxins; fungus, mycotoxins, bacteria, virus, toxic metals, radioactive metals, mycoplasma, chemicalsKey toxins; fungus, mycotoxins, bacteria, virus, toxic metals, radioactive metals, mycoplasma, chemicals The gutThe gut Mitochondrial functionMitochondrial function Homeopathic and naturopathic approaches Homeopathic and naturopathic approaches

April 2005 Ark International Training Seminars Further studies For further information: For further information: to Richard or Karen at ark- to Richard or Karen at ark- Look on web on web Ring Ring Write to 144 Cloudesley Road, Islington, London N1 0EAWrite to 144 Cloudesley Road, Islington, London N1 0EA

April 2005 Ark International Training Seminars References Matrix and matrix Regulation Matrix and matrix Regulation Pischinger; Haug ISBN Pischinger; Haug ISBN Homotoxicology and Ground Regulation System Homotoxicology and Ground Regulation System Hartmut Heine; Aurelia-Verlag ISBN Hartmut Heine; Aurelia-Verlag ISBN Molecular Biology of the Cell Molecular Biology of the Cell Alberts et al; Garland Science; ISBN Alberts et al; Garland Science; ISBN Clinical Rheumatology: Neuroendocrine Immune Mechanisms of Rheumatic Diseases Clinical Rheumatology: Neuroendocrine Immune Mechanisms of Rheumatic Diseases Chikanza; Balliere Tindall ISBN Chikanza; Balliere Tindall ISBN