1. Cytokines Chemotaxis - Elective Course 2016 – EM-ED
Dr. habil. Kőhidai László
Assoc. Professor
Dept. Genetics, Cell- and Immunobiology
Semelweis University
Chemotaxis - Elective Course
2016 – EM-ED

2. Cytokines - Definition
”Cytokine” (Cohen 1974):
Molecules capable for chemical communication between cells;
Most of them are growth factors or differentiation inducers;
Regulators of embryogenesis, haematopoesis, tissue ‘repair’, inflammatory and immune functions. E.g. normal growth and development, wound healing.
Lymphokines, monokines, chemokines

3. Characterization of cytokines Summary
Proteines / glycoproteines
Work in solved form
Low M.W.
Inducibility
Effects elicited on low cc.
Narrow spectrum
Specific receptors
Network
Multifunctionality
Synergy
Progression factor
Competency factor

4. Grouping - Functions Natural immunity and inflammation
(IFN, TNF, IL-1, IL-6, chemokines)
Regulating of lymphocyte activity,
differenctiation
(IL-2, IL-5, IL-6)
Maturation of immune cells
(IL-3, GM-CSF)

5. Characteristics Low M.W. 15-25kDa
Products of leukocytes – BUT other cells can also produce them
Production induced by
infectious substances and toxins (e.g. LPS)
tissue damage (thrombocyte aggregation)
immune iductions (stages of hypersensitivity)
other cytokines e.g. IL-1 (pro-inflammatory cytokines)
Constitutive – e.g. IL-16, IL-18, EPO, M-CSF

6. Characteristics
Majority of cytokines are released by the cells before action
BUT there are
membrane bound forms (TNF),
pooled in i.c. vesicles i.c. (mast cells vagy thrombocyte)
stored in extra-cellular matrixban (TGF-beta) – rapid release and action
Narrow action radius
autocrine – cytokine produced by the cell acts on the producer cell
paracrine – cytokine acts on the neighbour cells of the producer cell
endocrine – cytokine acts on cells far from the producer cell
IL-1 from site of injury to thalamus – regulation of temperature
IL-6 from site of injury to liver – acut phase reaction
Erythropoetin from kidney to bone marrow – RBC differentiation

7. IL-1 Macrophage T cell Brain Cytotoxicity ^ Activation ^
Monokine prod. ^
Adhesion mol. ^
Autocrine
Paracrine
Activation ^
IL-2R ^
Lymphokines ^
Endocrine
Brain
Prostaglandins
Pain threshold
Fever

8. Characteristics Effects on low concentrations : 10-12 – 10-9 M
! 10 IL-1 molecules are enough to induce IL-2 synthesis in T cells !
! 50 IFN gamma molecules are enough to induce anti-viral effects !

9. Receptors Specific receptors: high affinity, inducibility,
specific intracellular signal-transduction and
second messenger pathways.

10. Cytokine networks: cytokines are never produced
alone, their synthesis is controlled by the balance of
positive and negative signals.

11. inflammation Defense against infections Immune- Autoimmunity,
suppression
Autoimmunity,
rejection

12. Characteristics
Synery : combined effetc of two or more cytokines is higher than the simple summary of the individual effects
Antagonism : cytokines can block each other e.g. IL-4 and IFN-g.
Multifunctionality: (pluripotent , pleiotrope)
several cytokines possess more, different effects on the diverse target cells
Progressive factor:
cytokines induce cell proliferation
(IL-2, IL-3, IL-5)
Competency factor:
inducing of differentiation (IL-1, IL-4, IL-6)

13. Nomenclature Factors (names) describe the function - Historical
colony stimulating factor CSF
tumor necrosis factor TNF
transforming growth factor TGF
Classification based on characteristic gene sequence
– result of joint agreement
IL-1 – IL-24
Names describing the structure and function
chemotactic factors - ‘chemokins’.

14. Regulation Target cell DNA-level
genes turned on continously e.g. M-CSF, G-CSF, SCF, IL-6, Epo génjei
other genes of cytokines are turned off
co-ordinated expression e.g. IL-3, IL-4, IL-5, GM-CSF genes on 5. Chrs q
Post-transcription level
Post-secretion level
short half life time in serum e.g. TNF = 15min
soluble cytokine receptors, e.g. sTNF-R
Target cell
up- and down-regulation of receptors
induction or amplification of inflammation by i.e. pro inflammatory cytokines

15. Examples
IL-1 – produced by all cells possessing nucleus, its spectrum is wide, it has several target cells.
In vivo effects: hypotensio, fever, loss of weight, neutropoenia
and acut phase reaction.
The chief function is elicited as a factor released from dendritic cells.
Promotes proliferation of T lymphocytes.
IL-3 – haematopoetic growth factor, inducer of colony formation in erythroid, megakaryocyte, neutrophil, eosinophil, basophil, mast cell and monocyte cell lines.

16. Examples IL-6 – multifunctional cytokine, produced by lymphoid and
non-lymphoid cells. Regulator of B-cell funkcions, haematopoesis and the acut phasis reakction.
IL-8 - cytokine released in inflammation, several cells can produce it,
It works as chemoattractant in neutrophils.
Can also influence activity of basophils and some subpopulations
of lymphocytes.
Effective angiogen factor.

17. Examples
IL-12 – important in responses against intracellular pathogens.
Inducer of IFN gamma synthesis in T-cells and in NK cells.
Increases the NK and ADCC activity.
Inducer of proliferation and differentiation in Th1 CD4 cells.

19. Clinical significance
auto-immune diseases
infections
immune-defficiencies
malignant tumors