1、11 细胞因子及其受体,Cytokine and cytokine receptors,History for the research of the cytokines, In 1957，Interferon （IFN ） was found In 1969， termed lymphokine In1974，denominated cytokine cytokinology； international cytokine society Cytokine Companies for developing cytokines in many countries,Cytockines are
2、low-molecular-weight regulatory proteins or glycoproteins 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,由免疫细胞和某些非免疫细胞（如血管内皮细胞、表皮细胞和成纤维细胞等）经刺激而合成分泌的一类小分子量可溶性糖蛋白或蛋白多肽。,细胞因子 (cytokine),Cyt
3、okine gene,Inducing stimulus,Cytokine-producing cell,Cytokine,Gene activation,Receptor,signal,Biological effects,Overview of the induction and function of Cytokine,生物学效应：免疫细胞之间的信息交换及相互调节依赖于细胞因子。细胞因子除了介导、调节局部和全身免疫应答和炎症反应过程之外，还对伤口愈合、造血干细胞再生与分化密切相关。,-S-S-,-S-S-,-S-S-,CC C C,C1C3C2,C1C3C2,C1C3C2,C1C3C2,
4、G 蛋白,细胞因子受体,Biological effects ： Regulation and transfer of the information between the immune cells ;Mediation and regulation of the immune response and inflammation;Relationship with the wound healing , the regeneration and differentiation of the hemopoietic stem cells,-S-S-,-S-S-,-S-S-,CC C C,C1C
5、3C2,C1C3C2,C1C3C2,C1C3C2,G 蛋白,cytokine receptors,Biological effects of the cytokines,Anti-infection and antitumorImmune regulationapoptosisStimulating the proliferation and differentiation of hemopoietic stem cellsPromote the growth and differentiation of various cellsParticipation and regulation of
6、 the inflammatory responsesCytokine abnormalities in the pathogenesis in certain diseases Participation of the never-endocrine-immunity net,细胞因子的主要生物学效应,抗感染和抗肿瘤作用免疫调节作用参与细胞凋亡刺激造血细胞增埴分化促进各种细胞的生长和分化参与和调节炎症反应细胞异常可导致疾病的发生参与神经-内分泌-免疫网络,参与免疫应答与免疫调节 免疫应答识别（感应）阶段IFN刺激APC MHC-II的表达IL-1辅助T细胞活化IL-10抑制抗原递呈免疫应答细
7、胞扩增阶段IL-2、IL-4、IL-5、IL-6等促进T、B细胞的增殖与分化TGF- b 抑制淋巴细胞增殖,参与神经-内分泌-免疫网络细胞因子对神经内分泌：IL-1、IL-6、TNF 等直接参与神经系统的正常发育和损伤修复IL-1、TNF、IFN-g、PAF等诱导垂体释放ACTH，进而促进肾上腺皮质激素的释放应激时儿茶酚氨和糖皮质类固醇分泌增多，进而抑制IL-1、TNF的合成。在免疫应答过程中，免疫细胞之间通过细胞因子相互刺激、彼此约束，对免疫应答进行调节，维持免疫系统的稳态平衡。,1.白细胞介素(interleukin,IL) 2.集落刺激因子（colony stimulating fact
8、or,CSF).3.干扰素（interferon,IFN)4.肿瘤坏死因子（tumor necrosis factor,TNF)5.趋化因子（chemokine) 6.生长因子(growth factor,GF),细胞因子的种类,Interleukin, IL interleukins are secreted by some leukocytes and act upon other leukocytes, IL-1IL-23 have been identified.Colony stimulating factor, CSF The cytokines that stimulate he
9、mopoietic cells to form cell colony, Participate hemopoietic function are called CSF, for example GM-CSF,G-CSF,M-CSF, Epo,Tpo,GM-CSF,具有干细胞集落刺激活性的细胞因子,主要产生细胞,作,用,SCF,纤维母细胞，肝细胞，内皮细胞，,上皮细胞，基质细胞,所有类型的造血干细胞，黑色素,细胞，肥大细胞,IL-3,T,细胞,中性粒细胞，单核细胞，红细胞，,嗜碱性粒细胞,IL-5,T,细胞,嗜酸性粒细胞,IL-11,基质细胞，纤维母细胞,所有类型的造血干细胞，血小板,GM-C
10、SF,T,细胞，单核细胞，内皮细胞，纤,维母细胞,中性粒细胞，单核细胞，嗜酸性,粒细胞，树突细胞,G-CSF,单核细胞，纤维母细胞，,中性粒细胞,M-CSF,单核细胞，淋巴细胞，纤维母细胞，,内皮细胞，上皮细胞,单核细胞，胎盘滋养细胞,EPO,肾脏细胞,红细胞,TPO,肾，肝,血小板,集落刺激因子的作用,Interferon,IFN the cytokines that resist viral infection, and interfere viral replication, including IFN, IFN( type I); IFN( type II )Tumor necrosi
11、s factor,TNF the cytokines that induce directly apoptosis of tumor cells, including TNF, TNF (Lymphotoxin, T） , FASL, CD70L, 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
12、 factor，vascular endothelial growth 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,11-1 main properties of the cytokines,autocrine,endoc
13、rine,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,Bind to receptors on the membrane of the same cell that secreted it,肥大细胞,胸腺细胞,B,IL-4,活化、增殖、分化,增殖,增殖,2. 多效性pleiotropy,IL-2、 IL-4、 IL-5,
14、IL-4 + IL-5,B细胞,IL-4,IFN-,5. 拮抗性antagonism,3. 重叠性redundancy,4.协同性synergy,均有刺激B细胞增殖的功能,更有效地诱导IgE类别转换,IL-4 阻断IFN- 诱导类别转化的作用,B,B,B,On stimulation, rapid synthesis , release , action and degragation.,6. rapidity,7. high potency,Infinitesimal cytokines perform remarkable biological effects（pM,10-12 M).,细
15、胞因子受体,免疫球蛋白超家族（IgsF）造血细胞因子受体超家族（HCKRsF）趋化因子受体超家族（ChRsF）TFN受体超家族（TNFRsF）IFN受体家族,Soluble cytokine receptors (sCKR),Producing matter: Most of them break off from the member receptors Secrete receptor,IL-1IL-6IL-12 和 IL-18TNF,11-2 The cytokines produced by macrophages,1. activating T cells2. stimulating
16、 proliferation of B cell and antibody secreting3. inducing acute 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 necrosis factor,TNF,Two types:,TNF
17、-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, IL-4, g IFN,CSF) and expression of IL-2 receptor,TNF-a,Inducing differentiation up-regulation of antibody production,
18、Up-regulation of production prostaglandin and cytokines (IL-1, IL-6,IL-8,GM-CSF),Chemotaxis and 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 细 胞 的 分 化,Th1-Th2 分 泌 细 胞 因 子
19、 的 相 互 调 节 及 其 效 应,B细胞,IgG 2a,Tc 细胞 活化,巨噬细胞 活化,B细胞,IgM ，IgG 1， IgA， IgE,肥大细胞生长,嗜酸性粒细胞生长与分化,B 细胞，巨噬细胞,Th2细胞，肥大细胞,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-5 IL-6,Th1,Th1,APC,Mj,呈递抗原
20、,抗原,活化T细胞（IL-2产生的前体细胞）,Th1,增殖分化并分泌抗体,Th1,Th1,B,抗原刺激,分化,复制,IL-2反应细胞 （TH 或TC 细胞）,IL-2 的 生 物 学 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,proliferation, differentiation Secretion of antibody,Th1,Th1,B,antigen,differenti
21、ation,replication,IL-2 reactive cells （Th or TC ）,Immune bioactivities of IL-2,Type I interferon ：IFN-, IFN- 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 app
22、lication,related diseases ： deficiency of cytokines and receptors overexpression of cytokines high lever of soluble cytokine receptorsTherapeutic use of cytokines and their receptors： supply and addition blockage and antagonist,Common diseases,Infectious diseasestumorPlantation rejectionhematocytope
23、niahypersensitivityAutoimmune diseases,细胞因子引起的病理反应,大剂量TNF注射造成恶液质的小鼠模型,细胞因子与临床治疗,细胞因子抑制剂的临床应用 可溶性TNF受体治疗类风湿关节炎 IL-1受体拮抗剂（IL-1ra）治疗类风湿关节炎 DAB389-IL-2免疫毒素治疗T细胞淋巴瘤 抗TNF抗体治疗肠道自身免疫炎症,细胞因子抑制剂 用于治疗炎症，自身免疫病，移植排斥，休克,进入临床实验的细胞因子抑制剂,已批准上市的细胞因子基因工程药物,正进行临床试验的细胞因子基因工程药物,11-7 细胞因子调节网络,IL-6刺激APC 活化B细胞,IL-8趋化中性粒细胞,P
24、DGF纤维母细胞等的增殖,TGF-b 伤口愈和，抗炎，血管发生,IL-1T细胞活化APR刺激,TNF-a细胞毒作用，刺激细胞因子的分泌，MHC分子的合成,IL-11,G-CSF,M-CSF,GM-CSF造血,IL-12活化NK细胞，TH1/TH2细胞分化,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-a GM-CSF G-CMF M-CSF,单核细胞,中性粒细胞,嗜酸性粒细胞,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,内皮细胞,IL-4,IL-4,IL-2 IFN-g,IL-10 IL-13 IL-4,NK1+T,NK 细胞,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,内皮细胞,纤维母细胞,下 丘 脑,IL-1 TNF-a,M-CSF GM-CSF,IL-1 IL-6 TNF-a,IL- 4,IL- 6,IL- 4,
