1、Cytokines，CKsCytokinesConcept Characteristics Classification Cytokine receptorBiologic activityIntroduction to cytokinesWhat are cytokines ？ Cytokines are small proteins that are secreted by cells and exert their biological activity through specific cell surface receptors. Introduction to cytokineIn

2、troduction to cytokineDiffer from growth factors that cytokines involved in host defense that act on white blood cells (leukocytes), whereas growth factors act on other somatic cell types .Differ from growth factors that are produced constitutively, while cytokine production is carefully regulated I

3、ntroduction to cytokineNomenclature monokine,lymphokine,colony stimulating factor, interleukin, interferon, tumor necrosis factor,growth factor, chemokineManner of action 1)paracrine:IL-2 2)autocrine:IL-12 3)endocrine:IL-1Cytokines can act in three different mannersAutocrineCytokine binds to recepto

4、r on cell that secreted itParacrineCytokine binds to receptors on nearby cellsEndocrineCytokine binds cells in distant parts of the bodyIntroduction to CKsGeneral properties of CKs 1.Small proteins (MW:approx. 15-30 KD); 2.Extremely potent, acting at pM or fM 3.The production is transient and tightl

5、y regulated; 4.Autocrine , paracrine or endocrine; 5.Non-specific and non-MHC restriction； 6.Diversity in actionsIntroduction to CKsCytokine Actions Pleiotropy:Act on more than one cell type (IFN- / )Redundancy:More than one cytokine have the same action (IFN- / and IFN- )Introduction to CKsCytokine

6、 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 CKsCytokine Actions Cytoki

7、ne cascade A cytokine may increase (or decrease) the production of another cytokineIntroduction to cytokineThe 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.Figure：cytokines networkHow can

8、 non-specific cytokines act specifically?Only cells expressing receptors for specific cytokines can be activated by themMany cytokines have very short half-livesOnly cells in close proximity will be activatedHigh concentrations of cytokines are needed for activationOnly cells in close proximity will

9、 be activatedMay require cell-to cell contactCategories of CKsInterleukin (IL)Interferon (IFN)Tumor necrosis factor (TNF)Colony stimulating factor (CSF)ChemokineGrowth factor(GF) Cytokine receptor (CR)1.Five familiesIg superfamily receptorsClass I cytokine receptor family Class cytokine receptor fam

10、ilyClass cytokine receptor family (TNF receptor family)Chemokine receptor familyCK receptorMulti-subunit receptor one for cytokine binding another for cytokine signalingCommon receptor subunit There is same receptor subunit for cytokine signaling among the different cytokine receptors. e.g. IL-2R CK

11、 ReceptorSignal Transduction by cytokine receptorsCytokine receptors on different cell types trigger different eventsinterleukin, ILIL 133 IL-2（T cell growth factor） IL-4（ Th2 type） IL-6（ B cell growth factor , Th2 type ） IL-8（ chemokine） IL-10（Th2 type） IL-11（stimulator of platelet） IL-12（Th2 type）

12、IL-2IL-4IL-12interferon, IFNIFNs mediate the early innate immune response;groups type I IFN: IFN- and IFN-. The major source is leukocyte, fibroblasts and virus infected cells； type II IFN : IFN- . IFN- is mainly produced by activated T cells and NK cells.Interferon ActionViral replication stimulate

13、s the infected host cell to produce interferon. Interferon induces uninfected cells to produce antiviral proteins that prevent translation of viral mRNAdegrade viral nucleic acidViral replication is blocked in uninfected cellsTumor necrosis factor, TNFTNF: cause the necrosis of tumors TNF-and TNF-.

14、TNF- was produced by LPS-stimulated mononuclear phagocytes and activted T cells；TNF-：also termed as lymphotoxin ( LT），and the major source is activated T cells.Colony-stimulating factor, CSFStimulating the differentiation and expansion of bone marrow progenitor; be assayed by their ability to stimul

15、ate the formation of cell clones in culture.Including IL-3, CSF(G-CSF, M-CSF, GM-CSF), SCF, EPO, TPO, etc .ChemokineChemokines 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 ch

16、emokines. subfamily: CXC, CC, C, CX3C, based on structural characteristic (cysteine residues).ChemokineIL-8 CXC neutrophils MCP-1 CC monocyte Lymphotactin C lymphocyte Fractalkine CX3C lymphocyteGrowth factor(GF)Promoting the proliferation and differentiation of cells;Including TGF-、EGF、VEGF、FGF、NGF

17、、PDGF , etc.Biologic actions of CKsMediate and regulate innate immunityMediate and regulate adaptive immunityInduce apoptosis of cellsStimulate hematopoiesis1. Mediate and regulate innate immunityProtect against viral infection：type I IFN, IL-12, IL-15;pro-inflammatory cytokine：including TNF, IL-1 a

18、nd IL-6;TNF：cause vascular endothelial cells to express adhesion molecules；stimulate phagocytes to secrete chemokines；activate neutrophiles and Mo. to eradiate microbes;IL-10 is an inhibitor of immune response (It can inhibit many functions of activated M and T cells)2 Mediate and regulate adaptive

19、immunityStimulating the proliferation of lymphocytes： IFN- APC expressing MHC-II， IL-2 proliferation of T lymphocytes， IL-4 B lymphocytes， IL-5 eosinocyte, etc2Mediate and regulate adaptive immunityStimulating the development of lymphocytes： IL-12, IFN- Th1；IL-4 Th2 and Ig class switch；Increasing th

20、e activity of effective cells：IFN- Mo, M ; IFN- , IL-2 NK ; IL-2 CTL 。Inhibiting immune response： TGF- T cells and M .Cytokine secretion and biological activities of Th1 and Th2 SubsetsType 1Type 2IL-2IFN-TNFIL-4IL-5Cell-mediatedImmune response(intracellularOrganisms)Humoral response(parasites)T cel

21、lRole of TH1/TH2 balance in determining disease outcomes Balance of two subset determines response to diseaseLeprosyTuberculoid (TH1, CMI response, patient lives)Lepromatous (TH2, humoral response, patient dies) Comparative Features of the Cytokines of Innate and Adaptive ImmunityCyclosporineFeature

22、sInnate immunityAdaptive immunityExamplesTNF-, IL-1, IL-12, IFN- *IL-2, IL-4, IL-5, IFN- *Major cell sourceMacrophages, NK cellsT lymphocytesPrincipal physiologic functionsMediators of innate immunity and inflammation (local and systemic)Adaptive immunity: regulation of lymphocyte growth and differe

23、ntiation; activation of effector cells (macrophages, eosinophils, mast cells)StimuliLPS (endotoxin), bacterial peptidoglycans, viral RNA, T cell-derived cytokines (IFN-)Protein antigensAmounts produced Local or systemic effectsMay be high; detectable in serum BothGenerally low; usually undetectable in serum Usually local onlyRoles in diseaseSystemic diseases (e.g., septic shock)Lo