Cytokines

1. Cytokines Dr. habil. Kőhidai László Assoc. Professor Dept. Genetics, Cell- and Immunobiology Semelweis University Chemotaxis - Elective Course 2010/2011 – 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. 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 Characterization of cytokinesSummary

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 cytokinese.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-1from site of injury to thalamus – regulation of temperature IL-6from site of injury to liver– acut phase reaction Erythropoetinfrom kidney to bone marrow – RBC differentiation

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

8. Characteristics • Effects on low concentrations : 10-12– 10-9M ! 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. Defense against infections inflammation Immune- 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 factorCSF • 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 • DNA-level • genes turned on continouslye.g. M-CSF, G-CSF, SCF, IL-6, Epo génjei • other genes of cytokines are turned off • co-ordinated expressione.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 serume.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 vivoeffects: hypotensio, fever, loss of weight, neutropoenia and acut phasereaction. The chief function is elicited as a factor released from dendritic cells. Promotes proliferation of T lymphocytes. IL-3– haematopoeticgrowth factor, inducerof colony formationin 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,haematopoesisand theacut 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 angiogenfactor.

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

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