Chapter 7 Cytokines (CKs)

Contents  Part Ⅰ Definition and general properties of cytokines  Part Ⅱ Classification of cytokines  Part Ⅲ Cytokine receptor  Part Ⅳ Biological functions of cytokines  Part Ⅴ Cytokine and disease

Part Ⅰ Definition and general properties of cytokines Ⅰ. Definition A group of low molecular weight polypeptides or proteins which are secreted by activated immunocytes or some matrix cells and possess high activity and various functions. Their major functions are to mediate and regulate immune response and inflammatory reactions.

Ⅱ. General properties of cytokines 1.Most cytokines are low molecular weight polypeptides or glycoprotein(8~80 KD), and most of them are monomer. Monomer, dimer, trimer Soluble, membrane-bounded

2. Natural cytokines are secreted by activated cells Such as activated immune cells,matrix cells and some tumor cells. Ag, SAg, mitogen

3. One kind of cytokines can be produced by different cells. One kind of cells can secrete different cytokines. IL-3,GM-CSF,TNF-  IL-2 IFN-γ, TNF-β IL-4, 6 IL-5 Th1Th2

4. Cytokines act on target cells by the way of paracrine, autocrine or endocrine. Cytokines can act on the cells that produce them (autocrine), on other cells in the immediate vicinity (paracrine), or on cells at a distance (endocrine) after being carried in blood or tissue fluids.

5.Cytokines initiate their actions by binding to specific membrane receptors on target cells. Receptors for cytokines often bind their ligands with high affinities. Kd Antibody and antigen: Kd MHC-peptide and TCR: Kd

Low concentration (pmol/L) Most cells express low levels of cytokine receptors, and this is adequate for inducing response. So only small quantities of cytokines are needed to occupy receptors and elicit biologic effects.

6. The effects of cytokines are often pleiotropism, redundant, synergy, antagonism, and form a cytokine network. Pleiotropism refers to the ability of one cytokine having multiple effects on diverse cell types.

Redundancy refers to the property of multiple cytokines having the same or overlapping functional effects.

Synergy refers to the property of two or more cytokines having greater than additive effects.

Antagonism refers to the ability of one cytokine inhibiting the action of another.

TH1TH1 MM IL- 4 骨髓基质细胞 IL-1 IL-6 IL-7 SCF 造血干细胞 IL-1 IL-6 IL-11 TNF-  GM-CSF G-CMF M-CSF 单核细胞 TH2TH2 B 中性粒细胞 嗜酸性粒细胞 IL-1 IL-8 TNF-  IL-1 TNF-  IL-10 IL- 4 IL- 4 IL-6 IL-10 IL-13 IL-4 TGF-  IL-4 IL-5 IL-6 IL-13 IL-10 TGF-  IL-4 内皮细胞 IL-4 Tc IL-4 IL-2 IFN-  IL-10 IL-13 IL-4 NK1 + T NK 细胞 IFN-  IL-2 IL-2 IFN-  IL-2 IL-2 IL-12 G-CMF IFN-  GM-CSF IL-12 IL-1 TNF-  TGF-  PDGF FGF M-CSF GM-CSF 内皮细胞 纤维母细胞 下 丘 脑下 丘 脑 IL-1 TNF-  M-CSF GM-CSF IL-1 IL-6 TNF-  IL- 4 IL- 6 IL- 4

Part Ⅱ Classification of cytokines  Interleukin, IL  Interferon, IFN  Tumor necrosis factor, TNF  Colony stimulating factor, CSF  Chemokine  Transforming growth factor

Ⅰ. Interleukin (IL) Cytokines secreted by leukocytes that have the ability to act as signal molecules between different population of leukocytes IL-1~IL-38

Ⅱ. Interferon (IFN) A group of glycoproteins that produced by human or animal cells following the infection of virus and exposure to various inducing agents

Comparison of IFN- , IFN- , IFN-  _____________________________________ Types Produced cells Main functions ____________________________________ IFN-  leukocyte anti-virus,immune regulation IFN-  fibroblast anti-tumor IFN-  -- Type II Th1,NK weaker anti-virus effect stronger immune regulation effect anti-tumor _____________________________________ Type I

Ⅲ.Tumor necrosis factor (TNF) TNFs were originally thought of as selective antitumour agents, but are now known to have a multiplicity of actions.  TNF-  is produced mainly by LPS activated monocytes and macrophages.  TNF-  (lymphotoxin, LT) is produced mainly by activated Th0 and Th1.

Ⅳ. Colony-stimulating factors (CSF) Cytokines that stimulate proliferation or differentiation of pluripotent hematopoietic stem cell and different progenitors.  Multi-CSF (IL-3)  Granulocyte macrophage-CSF(GM-CSF)  Monocyte-CSF(M-CSF)  Granulocyte-CSF(G-CSF)  Stem cell factor(SCF)  Erythropoietin(EPO)

Ⅴ. Chemokine Chemokines are cytokines which recruiting monocytes,granulocytes and lymphocytes in blood to the sites of inflammation.  CXC chemokines(α subgroup):IL-8  CC chemokines(β subgroup):MCP-1  C chemokines(γ subgroup)  CX 3 C chemokines(δ subgroup) * C: cysteine; X: any amino acid

Ⅵ. Transforming growth factor Growth-factor are cytokines which stimulate the growth and differentiation of their target cells.  Transforming growth factor-  (TGF-  )  Epithelia growth factor(EGF)  Vascular endothelia cell growth factor(VEGF)  Fibroblastic growth factor(FGF)

Part Ⅲ CK receptor 1. Membrane-binding cytokine receptors: The receptor consists of extra-cellular region, trans-membrane region and cytoplastic region.

CK receptors can be grouped into five families according to structure and function: (1) Ig receptor superfamily:IL-1R,PDGFR,FGFR (2) Type Ⅰ CK receptor superfamily: CSFR (3) Type Ⅱ CK receptor superfamily: IFNR (4) Type Ⅲ CK receptor superfamily: TNFR (5) G-protein linked receptor superfamily: CCR5

High affinity IL-2R       Low affinity IL-2RModerate affinity IL-2R IL-2 IL-2 receptor

Three forms of the IL-2 Receptor (CD25)

Some cytokines use a common chain for signal transduction

2. Soluble cytokine receptor

Part Ⅳ Biological functions of cytokines 1.Take part in nonspecific immunity anti-bacteria, anti-virus 2. Take part in specific immunity 3. Stimulate hematopoiesis 4. Take part in inflammatory reaction

Part Ⅴ Cytokine and disease Cytokines and diagnosis: IL-3, CSF Cytokines and treatment: Th1/Th2/Th9/Th17/Th22/Treg Cytokines and disease prevention: CSF, IL-2 Cytokine assay: ELISA, flow cytometry

What should you know by the end of this lecture?  Definition of cytokine  General properties of cytokines  Classification and function of cytokines