Medical Immunology Cytokines ， CKs 陈建忠 浙江大学免疫学研究所

Cytokines Concept Characteristics Classification Cytokine receptor Biologic activity

Introduction to cytokines Cytokines (CKs) Cytokines are small proteins that are secreted by cells and exert their biological activity through specific cell surface receptors.

Introduction to cytokine Nomenclature Nomenclature Old ： monokine,lymphokine, Old ： monokine,lymphokine, New ： colony stimulating factor, interleukin, interferon, tumor necrosis factor,growth factor, chemokine New ： colony stimulating factor, interleukin, interferon, tumor necrosis factor,growth factor, chemokine

Introduction to CKs General properties of CKs 1.Small proteins (MW:approx KD); 2.Extremely potent, acting at pM or fM 3.The production is transient and tightly regulated; 4.Autocrine, paracrine or endocrine; 5.Non-specific and non-MHC restriction ；

Introduction to CKs Cytokine Actions Pleiotropy:Act on more than one cell type (IFN-α / β) Redundancy:More than one cytokine have the same action (IFN- α / β and IFN- γ)

Introduction to CKs Cytokine Actions Synergy:Two or more CKs cooperate to produce an effect that is different or greater than the combined effect of the two cytokines when functioning separately (IL-12 and IL-18) Antagonism:Two or more cytokines work against each other (IL-4 and IL-12)

Introduction to cytokine The CKs network It has been shown above that there are many CKs with multiple functions and apparent redundancy of action forming a complex communication network.

Cytokines network

Categories of CKs Interleukin (IL) Interferon (IFN) Tumor necrosis factor (TNF) Colony stimulating factor (CSF) Chemokine Growth factor(GF)

interleukin, IL IL 1 ～ 33 IL-2 （ T cell growth factor ） IL-4 （ B cell growth factor,Th2 type ） IL-6 （ Th2 type ） IL-8 （ belongs to chemokine ） IL-10 （ Th2 type ） IL-11 （ stimulator of platelet ） IL-12 （ Th2 type ）

IL-2

interferon, IFN IFNs mediate the early innate immune response; groups type I IFN: IFN-α and IFN-β. The major source is leukocyte, fibroblasts and virus infected cells ； type II IFN : IFN-γ. IFN-γ is mainly produced by activated T cells and NK cells.

IFN-  的 抗 病 毒 作 用 病毒 病毒复制 抑制病 毒复制 信号转导 IFN-  IFN- 诱导蛋白 诱导刺激 胞核

Tumor necrosis factor, TNF TNF: cause the necrosis of tumors TNF-αand TNF-β. TNF-α was produced by LPS-stimulated mononuclear phagocytes and activted T cells ； TNF-β ： also termed as lymphotoxin ( LT ）， and the major source is activated T cells.

Colony-stimulating factor, CSF Stimulating the differentiation and expansion of bone marrow progenitor; be assayed by their ability to stimulate the formation of cell clonies in culture. Including IL-3, CSF(G-CSF, M-CSF, GM-CSF), SCF, EPO, TPO, etc.

Chemokine Chemokines are a large family of structurally homologous CKs that stimulate movement and regulate the migration of leukocytes from the blood to tissues, including about 50 different chemokines. subfamiles: CXC, CC, C, CX3C, based on structural characteristic (cysteine residues).

Chemokine IL-8 CXC neutrophils MCP-1 CC monocyte Lymphotactin C lymphocyte Fractalkine CX3C lymphocyte

Growth factor(GF) Promoting the proliferation and differentiation of cells; Including TGF-  、 EGF 、 VEGF 、 FGF 、 NGF 、 PDGF, etc.

cytokine receptor cytokine receptor 1.Five families Ig superfamily receptors Class I cytokine receptor family Class Ⅱ cytokine receptor family Class Ⅲ cytokine receptor family (TNF receptor family) Chemokine receptor family

CK receptor Multi-subunit receptor one for cytokine binding another for cytokine signaling

CK Receptor Common receptor subunit There is same receptor subunit for cytokine signaling among the different cytokine receptors. e.g. IL- 2Rγ

CK Receptor

CK Receptors Soluble cytokine receptors Functions ： ① antagonist of CKs ； ② delivery tools of CKs ； ③ as a index of diagnosis and surveillance of diseases

Biologic actions of CKs Anti-bacteria: IL-1, TNF, IL-6, and IL-12, Anti-virus:type I IFN

Biologic actions of CKs Mediate and regulate adaptive immunity : Stimulating the proliferation of lymphocytes ： IFN- ,IL-2,IL-4,IL-5) Stimulating the development of lymphocytes: IL-12, IFN- ,IL-4. Increasing the activity of effective cells ： IFN- , IL-2. Inhibiting immune response: TGF- ,IL-10

Comparative Features of the Cytokines of Innate and Adaptive Immunity Cyclosporine FeaturesInnate immunityAdaptive immunity ExamplesTNF-α, IL-1, IL-12, IFN-γ *IL-2, IL-4, IL-5, IFN-γ * Major cell sourceMacrophages, NK cellsT lymphocytes Principal physiologic functions Mediators of innate immunity and inflammation (local and systemic) Adaptive immunity: regulation of lymphocyte growth and differentiation; activation of effector cells (macrophages, eosinophils, mast cells) StimuliLPS (endotoxin), bacterial peptidoglycans, viral RNA, T cell-derived cytokines (IFN-γ) Protein antigens Amounts produced Local or systemic effects May be high; detectable in serum Both Generally low; usually undetectable in serum Usually local only Roles in diseaseSystemic diseases (e.g., septic shock) Local tissue injury (e.g., granulomatous inflammation) Inhibitors of synthesisCorticosteroids, FK-506 *IFN-γplays important roles in innate and adaptive immunity.

Biologic actions of CKs Stimulate hematopoiesis SCF → stem cells CSF → granulocyte and monocyte IL-4 and GM-CSF →dendritic cells EPO → erythrocyte IL-11 and TPO →platelet IL-7 → formation of pro-T Angiogenesis

Biological product of cytokines or cytokines receptor analogs rIFN-α:Intron-A, Referon-A rIFN-β:Prokine rEPO:Epogen rGM-CSF:Acimmune Human TNF McAb:Humira TM