細(xì)胞因子及其受體

1、11 細(xì)胞因子及其受體,Cytokine and cytokine receptors,,,History for the research of the cytokines,? In 1957，Interferon （IFN ） was found ? In 1969， termed lymphokine ? In1974，denominated cytokine

2、 ? cytokinology； ?international cytokine society ?《 Cytokine 》 ? Companies for developing cytokines in many countries,Cytockines are low-molecular-weight regulatory proteins or g

3、lycoproteins secreted by white blood cells and various cells (vascular endothelial cell, epidermic cell and fibroblast ) in body in response to a number of stimuli.,Cytokine,由免疫細(xì)胞和某些非免疫細(xì)胞（如血管內(nèi)皮細(xì)胞、表皮細(xì)胞和成纖維細(xì)胞等）經(jīng)刺激而合成分泌的一類小

4、分子量可溶性糖蛋白或蛋白多肽。,細(xì)胞因子 (cytokine),Cytokine gene,Inducing stimulus,,Cytokine-producing cell,,,,,,,,,Cytokine,Gene activation,,,Receptor,signal,,,,,,Biological effects,Overview of the induction and function of Cytokine,生物學(xué)效

5、應(yīng)：免疫細(xì)胞之間的信息交換及相互調(diào)節(jié)依賴于細(xì)胞因子。細(xì)胞因子除了介導(dǎo)、調(diào)節(jié)局部和全身免疫應(yīng)答和炎癥反應(yīng)過(guò)程之外，還對(duì)傷口愈合、造血干細(xì)胞再生與分化密切相關(guān)。,,,,,-S-S-,-S-S-,-S-S-,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,CC C C,C1C3C2,C1C3C2,C1C3C2,C1C3C2,,,G 蛋白,細(xì)胞因子受體,Biological effects ：

6、 Regulation and transfer of the information between the immune cells ;Mediation and regulation of the immune response and inflammation;Relationship with the wound hea

7、ling , the regeneration and differentiation of the hemopoietic stem cells,,,,,-S-S-,-S-S-,-S-S-,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,CC C C,C1C3C2,C1C3C2,C1C3C2,C1C3C2,,,G 蛋白,cytokine receptors,Biological

8、 effects of the cytokines,Anti-infection and antitumorImmune regulationapoptosisStimulating the proliferation and differentiation of hemopoietic stem cellsPromote the growth and differentiation of various cellsParti

9、cipation and regulation of the inflammatory responsesCytokine abnormalities in the pathogenesis in certain diseases Participation of the never--endocrine-immunity net,細(xì)胞因子的主要生物學(xué)效應(yīng),抗感染和抗腫瘤作用免疫調(diào)節(jié)作用參與細(xì)胞凋亡刺激造血細(xì)胞增埴分化促進(jìn)各

10、種細(xì)胞的生長(zhǎng)和分化參與和調(diào)節(jié)炎癥反應(yīng)細(xì)胞異常可導(dǎo)致疾病的發(fā)生參與神經(jīng)-內(nèi)分泌-免疫網(wǎng)絡(luò),參與免疫應(yīng)答與免疫調(diào)節(jié) 免疫應(yīng)答識(shí)別（感應(yīng)）階段IFN刺激APC MHC-II的表達(dá)IL-1輔助T細(xì)胞活化IL-10抑制抗原遞呈免疫應(yīng)答細(xì)胞擴(kuò)增階段IL-2、IL-4、IL-5、IL-6等促進(jìn)T、B細(xì)胞的增殖與分化TGF- b 抑制淋巴細(xì)胞增殖,參與神經(jīng)-內(nèi)分泌-免疫網(wǎng)絡(luò)細(xì)胞因子對(duì)神經(jīng)內(nèi)分泌：IL-1、IL-6、

11、TNF 等直接參與神經(jīng)系統(tǒng)的正常發(fā)育和損傷修復(fù)IL-1、TNF、IFN-g、PAF等誘導(dǎo)垂體釋放ACTH，進(jìn)而促進(jìn)腎上腺皮質(zhì)激素的釋放應(yīng)激時(shí)兒茶酚氨和糖皮質(zhì)類固醇分泌增多，進(jìn)而抑制IL-1、TNF的合成。在免疫應(yīng)答過(guò)程中，免疫細(xì)胞之間通過(guò)細(xì)胞因子相互刺激、彼此約束，對(duì)免疫應(yīng)答進(jìn)行調(diào)節(jié)，維持免疫系統(tǒng)的穩(wěn)態(tài)平衡。,1.白細(xì)胞介素(interleukin,IL) 2.集落刺激因子（colony stimulating fac

12、tor,CSF).3.干擾素（interferon,IFN)4.腫瘤壞死因子（tumor necrosis factor,TNF)5.趨化因子（chemokine) 6.生長(zhǎng)因子(growth factor,GF),細(xì)胞因子的種類,,Interleukin, IL interleukins are secreted by some leukocytes and act upon other leukocytes, I

13、L-1~IL-23 have been identified.Colony stimulating factor, CSF The cytokines that stimulate hemopoietic cells to form cell colony, Participate hemopoietic function are called CSF, for example GM-CSF,G-CSF,M-CSF,

14、Epo,Tpo,,GM-CSF,,具有干細(xì)胞集落刺激活性的細(xì)胞因子,,主要產(chǎn)生細(xì)胞,作,,用,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,SCF,纖維母細(xì)胞，肝細(xì)胞，內(nèi)皮細(xì)胞，,上皮細(xì)胞，基質(zhì)細(xì)胞,所有類型的造血干細(xì)胞，黑色素,細(xì)胞，肥大細(xì)胞,,,,,,,,,,,,,,,,,,,,,,,IL-3,T,細(xì)胞,中性粒細(xì)胞，單核細(xì)胞，紅細(xì)胞，,嗜堿性粒細(xì)胞,,,,,,,,,,,,,,,,,,,,,,,IL-5,T,細(xì)胞

15、,嗜酸性粒細(xì)胞,,,,,,,,,,,,,,,,,,,,,,,IL-11,基質(zhì)細(xì)胞，纖維母細(xì)胞,所有類型的造血干細(xì)胞，血小板,,,,,,,,,,,,,,,,,,,,,,,GM-CSF,T,細(xì)胞，單核細(xì)胞，內(nèi)皮細(xì)胞，纖,維母細(xì)胞,中性粒細(xì)胞，單核細(xì)胞，嗜酸性,粒細(xì)胞，樹(shù)突細(xì)胞,,,,,,,,,,,,,,,,,,,,,,,G-CSF,單核細(xì)胞，纖維母細(xì)胞，,中性粒細(xì)胞,,,,,,,,,,,,,,,,,,,,,,,M-CSF,單核細(xì)胞，淋巴細(xì)胞

16、，纖維母細(xì)胞，,內(nèi)皮細(xì)胞，上皮細(xì)胞,單核細(xì)胞，胎盤(pán)滋養(yǎng)細(xì)胞,,,,,,,,,,,,,,,,,,,,,,,EPO,腎臟細(xì)胞,紅細(xì)胞,,,,,,,,,,,,,,,,,,,,,,,TPO,腎，肝,血小板,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,集落刺激因子的作用,,Interferon,IFN the cytokines that resist viral infection, a

17、nd interfere viral replication, including IFN?, IFN?( type I); IFN?( type II )Tumor necrosis factor,TNF the cytokines that induce directly apoptosis of tumor cells, including TNF?, TNF? (Lymphotoxin, T） , FASL, CD70

18、L, CD30L, CD40L, OX40L, TRAIL (TNF related apoptosis-inducing ligand,Growth factor the cytokines that promote growth of various cells, epidermal growth factor，insulin-like growth factor，vascular endothelial growt

19、h factorChemokine chemokines, a group of low-molecular-weight cytokinws including interleuki 8, that affect chemotaxis and other aspects of leukocyte behavior.,,,Chemokine causes the cellular morphologic alteration,

20、11-1 main properties of the cytokines,autocrine,endocrine,Binding to target cells in distant parts of the body.,paracrine,Binding to receptors on a target cell in close proximity to the producer cells,1. action manners,

21、Bind to receptors on the membrane of the same cell that secreted it,肥大細(xì)胞,胸腺細(xì)胞,B,,,,IL-4,活化、增殖、分化,增殖,增殖,2. 多效性pleiotropy,IL-2、 IL-4、 IL-5,,IL-4 + IL-5,B細(xì)胞,IL-4,IFN-?,5. 拮抗性antagonism,3. 重疊性redundancy,4.協(xié)同性synergy,

22、均有刺激B細(xì)胞增殖的功能,更有效地誘導(dǎo)IgE類別轉(zhuǎn)換,IL-4 阻斷IFN- ? 誘導(dǎo)類別轉(zhuǎn)化的作用,B,B,B,,On stimulation, rapid synthesis , release , action and degragation.,6. rapidity,7. high potency,Infinitesimal cytokines perform remarkable biological effects（pM,1

23、0-12 M).,,細(xì)胞因子受體,免疫球蛋白超家族（IgsF）造血細(xì)胞因子受體超家族（HCKRsF）趨化因子受體超家族（ChRsF）TFN受體超家族（TNFRsF）IFN受體家族,Soluble cytokine receptors (sCKR),Producing matter: ? Most of them break off from the member receptors ? Secrete r

24、eceptor,IL-1IL-6IL-12 和 IL-18TNF,,,11-2 The cytokines produced by macrophages,1. activating T cells2. stimulating proliferation of B cell and antibody secreting3. inducing acute

25、 phase response of liver4. inducing macrophage activation5. trigging inflammation and fever6. stimulating regeneration of hemopoietic stem cells,The functions of IL-1,macrophage,,,,,,,,,,IL-1,,TNF-a 157 aa,tumor necr

26、osis factor,TNF,Two types:,TNF-a,,TNF-b ( lymphotoxin- a, LT- a),TNF-b = LTa 171 aa,Activated macrophage,,,,,Homology 28%Same receptorsSame bioactivities,Activated T cell,Up-regulation of the cytokine production(IL-2,

27、 IL-4, g –IFN,CSF) and expression of IL-2 receptor,TNF-a,Inducing differentiation up-regulation of antibody production,Up-regulation of production prostaglandin and cytokines (IL-1, IL-6,IL-8,GM-CSF),Chemotaxis and

28、activation of neutrophil,Stimulating production of CSF Up-regulation of hemopoiesis,Bioactivities of TNF-a,11-3 cytokine produced by T cells,,IL-2,,,IFN-gIL-4IL-5IL-10,Th1 和 Th2 細(xì) 胞 的 分 化,Th1-Th2 分 泌 細(xì) 胞 因

29、 子 的 相 互 調(diào) 節(jié) 及 其 效 應(yīng),,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,B細(xì)胞,,IgG 2a,Tc 細(xì)胞 活化,巨噬細(xì)胞 活化,B細(xì)胞,,IgM ，IgG 1， IgA， IgE,肥大細(xì)胞生長(zhǎng),嗜酸性粒細(xì)胞生長(zhǎng)與分化,,,,,

30、,,,,,,,B 細(xì)胞，巨噬細(xì)胞,Th2細(xì)胞，肥大細(xì)胞,,,IL-12,IL-4,IL-10,IFN-g,Th1,IFN-g,IL-12,IL-4 , IL-110 , IL-13,IL-2,IFN-g,TNF-b,IL-12,IL-3 IL-4,Th2,IL-10,IL-5,IL-4,Immune bioactivities of IL-2,,,,,,,,,,,,,,,,,,,,,,,,,,,,,IL-1,g-IFN IL-4 IL

31、-5 IL-6,,,,,,,,,,Th1,,,,,,,,,,Th1,APC,,,,,,,,,,,,,,,Mj,,,,,呈遞抗原,抗原,,,,,,,,,,,,活化T細(xì)胞（IL-2產(chǎn)生的前體細(xì)胞）,,,,Th1,,,,,,,,,,,增殖分化并分泌抗體,,,,,,,,,,,,,,,,,,,,,,Th1,,Th1,,B,,,,,,抗原刺激,,分化,復(fù)制,IL-2反應(yīng)細(xì)胞 （TH 或TC 細(xì)胞）,IL-2 的 生 物 學(xué)

32、 作 用,,,,,,,,,,,,,,,,,,,,,,,,,,,,,IL-1,g-IFN IL-4 IL-5 IL-6,,,,,,,,,,Th1,,,,,,,,,,Th1,APC,,,,,,,,,,,,,,,Mj,,,,,Antigen presentation,antigen,,,,,,,,,,,,Activation of T cell ( precursor producing IL-2）,,,,Th1,,,,,,,,,,

33、,proliferation, differentiation Secretion of antibody,,,,,,,,,,,,,,,,,,,,,,Th1,,Th1,,B,,,,,,antigen,,differentiation,replication,IL-2 reactive cells （Th or TC ）,Immune bioactivities of IL-2,Type I interferon ：IFN-?, IFN

34、-? anti-virus,Type II interferon : IFN-?, immune regulation,interferon, IFN,CD8+T cell, CD4 + T cell, NK cell,,,Virus-infected cells,Immune biological effects of IFN-?,11-4 Cytokine and clinical application,related dise

35、ases ： deficiency of cytokines and receptors overexpression of cytokines high lever of soluble cytokine receptorsTherapeutic use of cytokines and their receptors：

36、supply and addition blockage and antagonist,Common diseases,Infectious diseasestumorPlantation rejectionhematocytopeniahypersensitivityAutoimmune diseases,細(xì)胞因子引起的病理反應(yīng),大劑量TNF?注射造成惡液質(zhì)的小鼠模型,細(xì)胞因子與臨床治療,細(xì)胞因子抑制

37、劑的臨床應(yīng)用 可溶性TNF?受體治療類風(fēng)濕關(guān)節(jié)炎 IL-1受體拮抗劑（IL-1ra）治療類風(fēng)濕關(guān)節(jié)炎 DAB389-IL-2免疫毒素治療T細(xì)胞淋巴瘤 抗TNF?抗體治療腸道自身免疫炎癥,細(xì)胞因子抑制劑 用于治療炎癥，自身免疫病，移植排斥，休克,進(jìn)入臨床實(shí)驗(yàn)的細(xì)胞因子抑制劑,,已批準(zhǔn)上市的細(xì)胞因子基因工程藥物,,正進(jìn)行臨床試驗(yàn)的細(xì)胞因子基因工程藥物,,11-7 細(xì)胞因子調(diào)節(jié)網(wǎng)絡(luò),IL-6刺激APC

38、 活化B細(xì)胞,,,IL-8趨化中性粒細(xì)胞,PDGF纖維母細(xì)胞等的增殖,TGF-b 傷口愈和，抗炎，血管發(fā)生,,,IL-1T細(xì)胞活化APR刺激,,,TNF-a細(xì)胞毒作用，刺激細(xì)胞因子的分泌，MHC分子的合成,,,IL-11,G-CSF,M-CSF,GM-CSF造血,IL-12活化NK細(xì)胞，TH1/TH2細(xì)胞分化,,,,,IL- 4,,骨髓基質(zhì)細(xì)胞,IL-1 IL-6 IL-7 SCF,,造血干細(xì)胞,IL

39、-1 IL-6 IL-11 TNF-a GM-CSF G-CMF M-CSF,單核細(xì)胞,中性粒細(xì)胞,嗜酸性粒細(xì)胞,,IL-1 IL-8 TNF-a,IL-1 TNF-a,,,IL-10 IL- 4,,IL- 4 IL-6,,IL-10 IL-13 IL-4 TGF-b,,,IL-4 IL-5 IL-6 IL-13 IL-10 TGF-b,,IL-4,IL-4,內(nèi)皮細(xì)胞,,IL-4,,IL-4,,IL-2 IFN-g,,

40、IL-10 IL-13 IL-4,NK1+T,NK 細(xì)胞,,IFN-g,,IL-2,,IL-2 IFN-g,,IL-2,,IL-2 IL-12,,G-CMF IFN-g GM-CSF,IL-12,,,IL-1 TNF-a TGF-b PDGF FGF,M-CSF GM-CSF,,內(nèi)皮細(xì)胞,纖維母細(xì)胞,下 丘 腦,,IL-1 TNF-a,M-CSF GM-CSF,,,IL-1 IL-6 TNF-a,,,IL- 4,IL