Cytokine : Hormone interrelationship

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. This complex communication occurs via two chemical substances:- Cytokines Cell surface molecules. April 2005 Ark International Training Seminars

Cell communication - The basis of life
This communication occurs as a: direct communication: adhesion molecules (cell-to-cell contact) indirect communication: cytokines (messenger substances) bound to specific receptor sites. 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 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 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
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Overview of inflammation:
Local inflammatory response Macrophages and monocytes initiate acute phase response (APR) The APR initiates 1st phase of inflammatory cytokines IL-1 TNF-a They activate the 2nd phase of cytokines that augment the shift in balance necessary for the inflammatory response IL-12 INF-a INF-b GM-CSF (Granulocyte-Macrophage Colony Stimulating Factor) Fibroblast growth factor April 2005 Ark International Training Seminars

Hormonal stimulation of pro-inflammatory cytokines

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 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 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 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 Th1 dominant diseases include: Hashmoto’s disease Type 1 diabetes Multiple Sclerosis Crohn’s disease Sarcoidosis 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 Chronic stimulation of Th2 leads to chronic allergic response and failure to respond to infection and cancer cells Th2 dominant diseases include: Allergies / atopy Inflammation 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

The defensive posture can be: excessive in part extreme antigen exposition over-stimulation lacking counter regulation inhibited in part 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 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. April 2005 Ark International Training Seminars

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. These cytokines are soluble glycoproteins that function as intercellular signalling molecules. The 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 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. April 2005 Ark International Training Seminars

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. April 2005 Ark International Training Seminars

Cellular inflammation: triggers
Cell type Trigger B-lymphocyte ACTH, b-endorphins, growth hormone, IGF-1 T-lymphocytes ACTH, b-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, b-endorphins, growth hormone, substance P April 2005 Ark International Training Seminars

Cellular inflammation: neuroendocrine regulation
Cytokine Effect TNF type (TNF-a, TNF-b, 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-b April 2005 Ark International Training Seminars

TNF type cytokines TNF-a, TNF-b, IL-1) They 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 response They increase ACTH They have a variable effect on prolactin except for IL-6 that increases prolactin They 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 IL-1a, IL-1b, TNF-a, IL-2 and IL-6 increases ACTH production Insulin decreases the action of most cytokines FGF and TGF-b decrease the action of most cytokines April 2005 Ark International Training Seminars

Cytokine & effects on hormones
ACTH prolactin Growth hormone TSH LH FSH IL-1a ? ↕ ↓ IL-1b ↑ TNF-a IL-2 IL-6 INF-g TGF-b PDGF April 2005 Ark International Training Seminars

Overview of inflammation

Most common stimuli for cytokine expression
Stress Psychological Allergies Chemical toxicity Toxic metal exposure Glycosylated protein Chronic subclinical infection Dysbiosis Radiation / electromagnetic Trauma Low oestrogen April 2005 Ark International Training Seminars

General activity of cytokines
Cytokines involved in acute inflammation TNF-, IL-1, IL-6, IL-8, IL-11 And other chemokines, G-CSF, and GM-CSF Cytokines involved in chronic inflammation They can be subdivided into: - Cytokines mediating humoral responses IL-4, IL-5, IL-6, IL-7, and IL-13 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). April 2005 Ark International Training Seminars

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

Pro-inflammatory cytokines
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 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) April 2005 Ark International Training Seminars

IL-1 activates adhesion molecules on vascular endothelium. (VCAM) 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. a potent mitogen for astroglial cells and induces astrocytes to synthesise NGF. interferes powerfully with the hypothalamic-hypophyseal-gonadal axis (HHGA). 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. April 2005 Ark International Training Seminars

Effect of IL-1 & TNF-a on cartilage

IL-2 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. 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. April 2005 Ark International Training Seminars

IL-2 Influence the maturation and differentiation of lymphocytes in the thymus and bone marrow. There are two major classes of lymphocytes: B 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. 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 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; 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. 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. The T lymphocyte has two receptor sites; the first site readily binds IL-2, 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 April 2005 Ark International Training Seminars

IL-2 Stimulates the proliferation of B cells, helping them to secrete antibodies 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. 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. [1] The Cancer Journal from Scientific American 1997; 3: Supplement 1 April 2005 Ark International Training Seminars

IL-2 ↑ lymphokine secretion 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 Stimulates fibroblasts to secrete extracellular matrix 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. 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-. April 2005 Ark International Training Seminars

IL-6 Stimulates the production of immunoglobulin producing B cells Stimulates proliferation of thymic and peripheral T cells 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. April 2005 Ark International Training Seminars

IL-6 Activates Natural Killer cells (NK cells). Induces breakdown of the extracellular matrix 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 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): 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. Major functions in neoplastic processes. IL-6 may affect cancer progression by its actions on:- Cell adhesion and motility Thrombopoiesis Tumour specific antigen expression 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. 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. 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. 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 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. 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. This provides a mechanism for a negative-feedback loop. April 2005 Ark International Training Seminars

IL-6 Oestrogen inhibits IL-6 expression. 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. April 2005 Ark International Training Seminars

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

IL-12 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 stimulatory effect of IL-12 on TH1 development is antagonised by IL-4, a cytokine that promotes TH2 cell development. Proinflammatory cytokine. Excess production can indicate infection, inflammation, autoimmune disease and cancer Found to be elevated in autism and MS 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. MHC 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. 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 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: 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. 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. April 2005 Ark International Training Seminars

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

IFN- and IFN- Both are generated by leukocytes and fibroblasts Their functions are : Antiviral properties. Interferon activates phagocytes. Anti-proliferative properties. Interferon 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. 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. 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). April 2005 Ark International Training Seminars

IFN- IFN- is generated by T-lymphocytes and Natural Killer cells Its functions are: Antiviral properties. The development of TH1 from TH0 cells and the inhibition of TH2 cells. 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. Stimulates the expression of VCAM. Stimulates the differentiation of cytotoxic T-cells. Inhibits IL-4. Promotes the synthesis of IgG2 by activated T cells over production of IFN- can be caused by toxins such as Epstein Barr virus [1] Multiple sclerosis (MS) is an autoimmune disease that might be mediated by T-cells that attack the myelin components of the CNS, specifically myelin basic protein (MBP) and proteolipid protein (PLP). When animals are injected with MBP or PLP plus adjuvant, a disease is induced that is similar to MS. There is strong evidence that MS develops in patients who have a myelin configuration resembling certain components of common viruses, in particular the measles virus. MS is more common and more difficult to treat in females than males, and it tends to run in families. It is chronic and progressive; patients are ultimately confined to wheelchairs or, in severe cases, bedridden. An estimated 300,000 Americans are afflicted with MS. Most are treated with diet and exercise. Steroids and other immuno-suppressants are reserved for acute exacerbation of the disease. Studies in the use of interferon- for MS were disappointing; the compound stimulated the immune system but exacerbated the MS. Interferon-b, on the other hand, appears to have an inhibitory effect on a hyperactive immune system, perhaps by moderating the activity of -interferon and might prove to be more successful. April 2005 Ark International Training Seminars

IFN-g-inducing factor: (IGIF)
It has been proposed that IGIF be designated as IL-18 Functions Induces IFN-g production more potently than IL-12 Induces the development of TH1 cells. Enhances of NK cell cytotoxicity Augments GM-CSF 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-a 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-a, 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. The production of acute phase proteins. The stimulation of the production of nitric oxide. If TNF-a is produced for long periods, then it produces cachexia. Destroys cells in the CNS that produce serotonin, leading to depression April 2005 Ark International Training Seminars

TNF- TNF-a and diet High levels of carbohydrates or fats increases activity of TNF High levels of protein does not increase activity of TNF-a. TNF-a when produced in low concentrations: Up-regulates the inflammatory response. Induces expression of ICAM-1, VCAM-1 and E-selectin. Enhances killing of intracellular organisms such as Leishmania and Mycobacterium tuberculosis. Activates leukocytes to produce IL-6 and TNF- itself. 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 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 stimulation of several PMN (polymorphonuclear leukocytes) effector functions. TNF-b lyses tumour cells. TNF-b activates neutrophils. TNF-b increases the adhesion of leukocytes to the vascular endothelium. 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; 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 Derived from T cells, platelets, and monocytes.: 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, 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 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-. April 2005 Ark International Training Seminars

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

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

IL-4 Responsible for the induction of CD8 Stimulates production of VCAM-1 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- Its actions are antagonised by IFN- and vice versa. It is a synergist with IL-3 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. Stimulates growth of eosinophils, which are responsible for killing the helminth family of parasites Stimulates the growth and differentiation of B-cells It induces the synthesis of IgA and IgM in mature B-lymphocytes Enhancement of T cell cytotoxicity 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. It is an anti-inflammatory cytokine along with IL-4 and IL-13. Down-regulates the macrophage production of IL-1, IFN- and TNF-. 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. It is over-expressed in some viral, bacterial and parasitic infections April 2005 Ark International Training Seminars

IL-10 Inhibits nitric oxide production. Stimulates B-cell proliferation. Inhibits macrophage/monocyte activation. 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 April 2005 Ark International Training Seminars

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

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

IL-8 Derived from phagocytes, antigen-activated T cells, endothelial and epithelial cells, and even neutrophils. 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. Stimulate granulocyte activity Up-regulates cell-surface adhesion molecule expression ↑ endothelial leukocyte adhesion molecule (ELAM-1) ↑ intracellular adhesion molecule, ICAM-1 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. Dependent on IL-4, IL-10 and IL-2. Promotes proliferation of T-cells – CH8 T cells. It inhibits lymphokine production by IFN--producing CD4+ T 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. 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. Induces IL-6 expression by CD4+ T cells. Promotes lymphopoiesis. Promotes the growth of haemopoietic cells. Stimulates T cell-dependent B cell immunoglobulin secretion, Stimulates platelet production. April 2005 Ark International Training Seminars

IL-14 Generated from T-lymphocyte and malignant B-lymphocytes. Induces proliferation of activated B-cells 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 R. Ford, A. Tamayo, B. Martin, K. Niu, K. Claypool, F. Cabanillas & J. Ambrus Jr: Identification of B-cell growth factors (interleukin-14; high molecular weight-B-cell growth factors) in effusion fluids from patients with aggressive B-cell lymphomas. Blood 86, (1995 April 2005 Ark International Training Seminars

IL-15 The human IL-15 gene has been mapped to chromosome 4, similarly to IL-2. 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. April 2005 Ark International Training Seminars

IL-15 Stimulates T-cell production by binding to IL-2 receptor sites Stimulates NK cell proliferation, as well as CTL and LAK activity. Enhances B cell expansion and immunoglobulin production. 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 April 2005 Ark International Training Seminars

IL-16: 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 induces chemotaxis of CD4+ T lymphocytes. Initiates T cell mediated inflammation in asthma. April 2005 Ark International Training Seminars

IL-17: Generated from activated T lymphocytes. Stimulates IL-6 and IL-8 production . Enhances ICAM-1 expression 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: Granulocyte-Colony Stimulating Factor G-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 both participate in acute inflammation. They both can stimulate neutrophils. 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. Potent stimulator of astrocyte proliferation. EGF is not synthesized by the developing neuronal cells, (but its homologue, TGF-a , is expressed in the brain.) 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. 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 molecules April 2005 Ark International Training Seminars

Fibroblast growth factors (FGFs)
The family of fibroblast growth factors (FGFs) include several forms They occur in many peripheral tissues. The brain and pituitary are rich sources of FGF-b 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, 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 IL-4 and IL-13 (stimulatory) and IFN-g (inhibitory) control IgE synthesis IL-1 and TNF-a up-regulation the expression of the endothelial adhesion molecule. April 2005 Ark International Training Seminars

Hormone regulation Hormone regulation: Upstream to the pituitary (stimulating hormones) and hypothalamus (regulating hormones Downstream via metabolic pathways in relationship to the cofactors in their synthesis Downstream 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 Oestrogen 18- carbon chain Androgens 19 carbon chain Progesterone 21 carbon chain 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) Corticotrophin releasing hormone (CRH) Anti-inflammatory The major stress response mediator of the CNS Immunosuppressive centrally under sympathetic stimulation Stimulated by oestrogen ACTH Responsible for cortisol production Immunosuppressive Hence capable of relieving symptoms of RA Gonadal androgens Inhibit IL-6, TNF-a, IL-1 production April 2005 Ark International Training Seminars

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

HPA axis DHEA Enhances IL-2 & INF-g production Enhance Th1 response Oestrogens Enhance Th1 & Th2 activity Prolactin Potent pro-inflammatory effects 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 April 2005 Ark International Training Seminars

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

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

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

Sex hormones and inflammatory process

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

Macrophage and T-cell pathways in RA

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

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

Hormone IL-1 TNF-a IL-6 INF-g 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 Inflammation Autoimmune disease Myocardial infarction Apathy Anorexia Weight loss Insomnia Weakness Loss of libido Pain Asthma Allergies Loss of mental concentration April 2005 Ark International Training Seminars

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

Inflammation and the Gut
Gut bacteria (2½ to 3 pounds weight) 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. 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 is an anti-inflammatory cytokine TNF a and IL-1b increased. 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: IL-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 pressure This is the case in acute inflammatory joint disease This can be the result of trauma, abnormal usage or infection April 2005 Ark International Training Seminars

PH 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. The fragments are then removed by macrophages. April 2005 Ark International Training Seminars

PH 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. 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. April 2005 Ark International Training Seminars

PH 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. 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 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). 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 Ovarium compositum and Tonsilla compositum Glandula suprarenalis suis-Injeel, Hypothalamus suis-Injeel and Funiculus umbilicalis suis-Injeel CNS imbalance Thalamus compositum Sleep disturbance Altered pain threshold April 2005 Ark International Training Seminars

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

Homeopathy: PATHOGENS
CELLULAR ECOLOGY. The primitive life of symbiotic organisms live in a strong alkaline pH, bacterial life forms live in a mild alkaline pH, fungal life forms live in a medium 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. 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: July 7th-9th RIBA, London Key toxins Pathogenic life forms Balance of pH environment Drainage remedies Enderlein remedies April 2005 Ark International Training Seminars

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

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

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

Cytokine : Hormone interrelationship

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