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Cytokines

Cytokines. Cell-to-cell communication Low-molecular-weight regulatory proteins In regulating the development of immune effector cells and some cytokines To act locally Bind to the specific receptors on target cell membrane

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Cytokines

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  1. Cytokines • Cell-to-cell communication • Low-molecular-weight regulatory proteins • In regulating the development of immune effector cells and some cytokines • To act locally • Bind to the specific receptors on target cell membrane • High affinity with dissociation constants ranging from 10-10 to 10-12 M • Action: autocrine, paracrine action, and endicrine action • Cytokine attributes: pleiotropy, redundancy, synergy, antaonism and cascade induction

  2. Overview of the induction and function of cytokines • The action of cytokines

  3. Cytokine Attributes

  4. Cytokines, Table 12-1 • Lymphokines: secreted by lymphocytes • Monokines: secreted by monocytes and macrophages • Interleukins: secreted by some leukocytes and act upon other leukocytes, such as Interleukin 1-18 • Interferons • Tumor necrosis factors • Chemokines • A group of low-molecular-weight cytokines including interleukin 8 • Affect chemotaxis and other interleukocyte behavior • Play important role in the inflammatory response

  5. Structure of Cytokines • Molecular weight less than 30 kDa • One of the hematopoietin family, interferon family, tumor necrosis factor family or chemokine family • The hematopoietin family: • High degree of -helix structure • Little or no -sheet structure • Share similar polypeptide fold

  6. *Cytokines: • as intercellular messenger molecules • *Two principle producer: • TH cell • macrophage

  7. Cytokine Receptors • Immunoglobulin superfamily receptors • Class I cytokine receptor family (hematopoietin receptor family): • function in immune and hematopoietic system • Four conserved cysteine residues (CCCC) • WSXWS conserved sequence • Class II cytokine receptor family (interferon receptor family) • Four conserved cysteine residues (CCCC) • No WSXWS conserved sequence • TNF receptor family • Chemokine receptor family

  8. Containing: • Cytokine-specific subunits • A signal-transducing subunit Three subfamily: GM-CSF receptor subfamily, IL-6 receptor subfamily, and IL-2 receptor subfamily

  9. Cytokine Receptors • Function: • Increase affinity for the cytokines • Transduce a signal across the membrane • GM-CSF receptor subfamily • Share a common signal-transducing  subunit, transdue a similar activation signal Antagonistic effect: Competition of lig-and-binding chains of different receptor

  10. Cytokine Receptors • IL-6 receptor subfamily • Signal-transducing subunit called gp130 • IL-2 receptor subfamily • IL-2 and IL-5 receptors are heterotrimers: cytokine + chain + chain  (chain  and chain  are responsible for signal transduction)

  11. Signal transduction mediated by cytokine receptors = A series of protein tyrosine phosphorylation

  12. STATs • Signal transducers and activators of transcription • Bind to the phosphorylated tyrosine residues • Play essential roles in the signaling pathways of cytokines

  13. Cytokine Antagonists • Inhibit the biological activity of cytokines • Bind to the cytokine receptor • Bind to the cytokine • Be found in the bloodstream and extracellular fluid • Some virus can produce cytokine-binding protein or cytokine mimics

  14. Cytokines from TH Cell • 依照T-help cells所製造的淋巴激素，將其分為三類：TH0、TH1、TH2。 （1）TH 1 cells：IL-2、IFNγ，to promote cell-mediated immune respone，augment IgM and IgG2 synthesis by B cells，activity macrophages。 （2）TH 2 cells：IL-4、IL-5，to promote antibody-mediated immune respone，lead to IgG1 and IgE responses，lead to increased numbers of local and/or circulating eosinophils ， support allergic reaction。 （3）TH 0 cells：IL-2、IFNγ、IL-4、IL-5。

  15. Important for TH1 cells Essential for TH2 cell development Stimulatory effects Inhibitory effects Regulation of TH subsets by cytokines

  16. Cytokine-Related Diseases • Bacterial septic shock • Cytokine overproduction • Bacterial cell-wall endotoxinsmarcophage to overproduce IL-1 and TNF- • Bacterial toxic shock and similar deases • Bacteria produce toxins that act as superantigens • The large number of T cells activated o result in excessive production of cytokines • Lymphoid and myeloid cancers • Cytokines and their receptors abnormally producted • IL-6 overproduction plasmacytosis cancer

  17. Therapeutic Use of Cytokines and Their Receptors

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