CYTOKINES Cytokines Lymphokines Monokines Interleukins Chemokines Growth Factors Tumor necrosis factors Hormones

Proliferation Differentiation Secretion (cytokines, antibodies)

(Juxtacrine)

Detection of cytokines: 1.Cytokine-specific cell proliferation (T H cell line dependent on Il-2) 2.ELISA 3.FACS – cytokines (intracellularly acting antibodies) 4.FACS – cytokine receptors 5.Elispot assay. 6.qRT-PCR

Cytokine-specific cell proliferation.

Capture ELISA

Elispot assay

Principal producers of cytokines: - T H cells - macrophages - dendritic cells. Activated T H cell

Nature 2007 October 18, 449 p 823

Processing of Il-1a. Il-1a is cleaved intracellularly by Ca-dependent calpain Cleavage exposes a nuclear localization signal and the active product enters the nucleus where it functions as a transcription factor. The intact protein functions as a DAMP molecule and when freed from the cytoplasm binds to and activates the IL-1R receptor.

TGF  -activated kinase

TRAF6: TNF  associated factor IRAK: Il-1 R activated Kinase TAK1: TGFb Activated Kinase 1.

Alpha helix bundle with helices pointing in opposite direction. Don’t confuse with anti- parallel beta-pleated sheet structure.

Interleukin 2

21

REDUNDANCY:(1) Stimulate hematopoietic stem cells, progenitors (2) Activate monocytes (3) Induce megakaryocyte differentiation (4) Eosinophil proliferation (5) Basophil degranulation

Il-3 receptor GM-CSF receptor Antagonism between IL3R and GM-CSF R

Leukemia- inhibitory factor Oncostatin M Ciliary Neurotrophic Factor Acute-phase proteins liver Differentiation macrophages Neuronal development Megakaryocyte maturation, platelet production

X-linked severe combined immunodeficiency (XSCID): IL-2R  deficiency

TAC CD25

IL-10 IN

SOCS: Suppressors of Cytokine Signalling SHP-1: Scr homology domain 2-containing phosphatase PIAS: Protein Inhibitor of Activated STAT

=CD70 binds to CD27 of activated T and B cells. L =CD95L or CD178 of CTL =CD153 binds to CD70 of T cells.

tBid = truncated Bid

Nature 2007n July 26, 448 p417 IL-23 is related to the Th-stimulating IL-12.

Phosphorylation of tristetraprolin

Chemokines (and their receptors): 1.CCL#ex. CCL11 (eotaxin), CCL5 (RANTES), CCL3 (MIP-1  ) 2.CXCL#ex. CXCL8 (interleukin 8) 3.CX 3 CL1 (fractalkine-transmembrane chemotaxin) 4.XCL1 (lymphotactin)

Cytokine antagonists: 1)Il-1R antagonist 2)Cytokine antagonists derived from cleavage of the cytokine receptor. 3)Viruses exploit cytokine activity: a)EBV (viral IL-10, inducer of IL-1Ra) b)Poxviruses: soluble Il-1 and TNFa binding proteins. c)Cowpox: Crm: cytokine response modifier inhibits caspase 1.

Cytokine-related Diseases: 1.Septic shock: macrophages – Il-1, TNFa 2.Toxic Shock syndrome: TH cells  INFg  macrophage activation: Il-1 and TNFa 3.Cytokine storm in infection 4.Cytokines in myeloid and lymphoid cancers. 5.Cytokines and metabolic syndrome

Jim Henson died in 1990 at age 54 from streptococcal TSSD.

Streptococcal Toxic Shock Syndrome

Metabolcs Syndrome/Type 2 Diabetes = decreased insulin response of cells [Glucose] Reactive Glucose (glyoxals) Impaired peripheral circulation Plaque buildup Heart disease Hypertrophic visceral fat/ adipocytes TNFa IL-6