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1、1,细胞因子,Cytokine,一、细胞因子导论 二、细胞因子参与的信号通路 三、几个重要细胞因子及其信号通路,2,目录,细胞因子在信号通路中的位置 细胞因子的定义 细胞因子的产生 细胞因子的命名和种类 细胞因子发挥作用的方式 细胞因子的共同特点 细胞因子的生物学效应 细胞因子受体,3,一、细胞因子导论,4,细胞因子在信号通路中的位置： 靶基因或者胞外信号,5,细胞因子作为胞外信号， 与激素和神经递质并列,内分泌系统 免疫系统 神经系统,6,由活化的免疫细胞和某些非免疫细胞经刺激而合成、分泌的一类小分子多肽，具有调节细胞生长、分化、成熟、调节免疫应答、参与炎症反应、促进伤口愈合以及肿瘤消长等功
2、能。,免疫球蛋白(抗体)、补体不包括在细胞因子之列。,细胞因子的定义,1.活化的免疫细胞 2.基质细胞: 3.某些肿瘤细胞,7,细胞因子的产生,血管内皮细胞、上皮细胞、神经胶质细胞、成纤维细胞,细胞因子相当于这些细胞中 信号通路的靶基因和最终产物。,NK细胞，natural killer cell，自然杀伤细胞,嗜碱性细胞在结缔组织和粘膜上皮内时，称肥大细胞,（一）根据产生细胞因子的细胞种类不同分类 淋巴因子（lymphokine) 单核因子（monokine） 非淋巴细胞、非单核-巨噬细胞产生的细胞因子 （二）根据细胞因子主要的功能不同分类 1.白细胞介素（interleukin,IL) 2
3、.干扰素（interferon,IFN) 3.集落刺激因子（colony stimulating factor, CSF) 4.肿瘤坏死因子（tumor necrosis factor, TNF) 5.趋化因子家族（chemokine family) 6.生长因子家族（growth factor family, GF),8,细胞因子的命名和种类,9,自分泌 autocrine,内分泌 endocrine,血液循环,远距离作用,旁分泌 paracrine,作用于比邻细胞,细 胞 因 子 发 挥 作 用 的 方 式： 旁分泌和自分泌为主,作用于分泌细胞自身,1.低分子量 2.多源性和多向性（产生）
4、 3.短时自限性 4.非特异性 5.高亲和力和高效性 6.多效性和重叠性 7.协同性、拮抗性和网络性 8.双重性,10,细胞因子的共同特点,分泌型小分子糖蛋白（MW60kD), 单链或双链，三聚体（TNF）,（1）有利：免疫调节、促进造血、抗感染、抗肿瘤 （2）有害：炎症、休克、发热、自身免疫病、肿瘤,通过与其受体结合而发挥效应，量微而作用强,无前体储存，刺激才合成，无刺激即停止，产物迅速被分解,（1）一种细胞可分泌多种细胞因子 （2）几种不同的细胞可产生一种或几种相同的细胞因子,一种细胞因子可以作用于不同的细胞，无抗原特异性和MHC限制性,11,肥大细胞,胸腺细胞,B,IL-4,多效性 pl
5、eiotropy,活化、增殖、分化,增殖,增殖,12,13,网络性,14,Biologic activity,1. Take part in innate immunity 2. Take part in adaptive immunity 3. Stimulate hematopoiesis 4. Mediate inflammation,15,先天性免疫,浆细胞 体液免疫,APC,Th：CD4+,Tc：CD8+,Th1细胞免疫,Th2,获得性免疫,血细胞,免疫细胞 （白细胞）,APC：antigen-presenting cell,16,IFN-a 的 抗 病 毒 作 用,病毒,病毒复制,
6、抑制病 毒复制,信号转导,IFN-a,IFN-诱导蛋白,诱导刺激,胞核,胞核,1. Take part in innate immunity,17,APC, antigen-presenting cell; IRF, IFN-regulatory factor; NK, natural killer; TCR,T-cell receptor; Bcl-6, B-cell lymphoma 6,2. Take part in adaptive immunity,定型细胞,18,Th1-Th2 分 泌 细 胞 因 子 的 相 互 调 节 及 其 效 应,B细胞,IgG 2a,Tc 细胞 活化,巨噬
7、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-4,19,20,3. Stimulate hematopoiesis,21,Modulation of in vivo inflammation by the D6 chemokine receptor decoy.,PMA：Phor
8、bol ester (佛波酯) T ：T lymphocytes E： neutrophils M： mast cells,4. Mediate inflammation,22,23,Cytokine receptors,Membrane-binding cytokine receptors (1) Immunoglobulin family （IGSF） (2) Type I cytokine receptor family （EPOR） (3) Type II cytokine receptor family （INFR） (4) Type III cytokine receptor fa
9、mily （NGFR，TNFR） (5) Chemokine receptor family （GPCR） 2. Soluble cytokine receptors,EPO：erythropoietin CRF：cytokine receptor family,CRF,24,25,Membrane-binding cytokine receptors,TKCR (CRF),ligand-receptor+TK,NRTK：Jak,EPOR,INFR,TNFR,Chemokine Receptor,26,Receptor of Growth factors（RTK）,27,28,common s
10、ubunits （共用信号链）,Common gamma chain：CD132 （gene：IL2RG ） Common beta chain gp130 意义：不同的细胞因子，相同的信号传导和生物学活性。,29,gp130,30,31,2. Soluble cytokine receptors Competitive inhibition Transporter of cytokine IL-1、IL-2、IL-4、IL-5、IL-6、IL-7、IL-8 G-CSF、GM-CSF、IFN、TNF,JAK-STATS MAPK（ERK、JNK、p38） NF-kB Apoptosis GPC
11、R,32,二、细胞因子参与的信号通路,33,Model of JAK-STAT signaling,JAK: just another kinase/janus kinase STAT: Signal transducers and activators of transcription Y： tyrosine phosphorylated S ：serine phosphorylated Prl, prolactin,RTK,NRTK,34,35,PRO：Prolactin，泌乳素 Epo：erythropoietin，促红素 Tpo：thrombopoietin，血小板生成素,36,37,
12、MAPK signaling cascades,ras,ras,38,NF-B,nuclear factor kappa-light-chain-enhancer of activated B cells,39,Discovery of NF-B,David Baltimore (Nobel Prize,1975),3 gene cluster heavy chain:1 light chain: 2 、,40,The steps in immunoglobulin gene rearrangement at which cells can be lost The developmental
13、program usually rearranges the heavy-chain (H-chain) locus first and then the light-chain (L-chain) loci. Cells are allowed to progress to the next stage when a productive rearrangement has been achieved. Each rearrangement has about a one in three chance of being successful, but if the first attemp
14、t is nonproductive, development is suspended and there is a chance for one or more further attempts. The scope for repeated rearrangements is greater at the light-chain loci , so that fewer cells are lost between the pre-B and immature B cell stages than in the pro-B to pre-B transition.,41,42,Schem
15、atic representation of members of the Rel/NF-B,DNA binding nuclear localization subunit dimerization,LZ, leucine zipper; TD, transactivation domain; GRR, glycine-rich region; PEST : proline (P), glutamic acid (E), serine (S) and threonine (T); DD, death domain;,Constitutive Selective,(p65),43,IKK ph
16、osphorylation sites: degradation,Schematic representation of members of the IB families of proteins,Mask the nuclear localization signals (NLS),44,One of the most common protein-protein interaction motifs in nature. 33-residue, two alpha helices,Ankyrin Repeat,repressors Homodimers of p50 and p52 ac
17、tivators Heterodimers with RelA, RelB, or c-Rel Homodimers of p50 and p52+Bcl-3,45,46,Figure 3 Model of different NF-B signalling pathways,secondary lymphoid organogenesis maturation of B-cells adaptive humoral immunity,Immune responses Inflammation Promoting cell survival,immune responses inflammat
18、ory responses,NEMO (IKK gamma) : NF-B essential modulator NIK: NF-B-inducing kinase,(IKK gamma),(NF-B-inducing kinase),1. INF Signaling 2. Chemokine Signaling 3. TNF Signaling 4. IL Signaling,47,三、几个重要细胞因子及其信号通路,Interferons play an important role in the first line of defense against viral infections
19、. They are part of the non-specific immune system and are induced at an early stage in viral infection before the specific immune system has had time to respond. Interferons are made by cells in response to an appropriate stimulus, and are released into the surrounding medium. They then bind to rece
20、ptors on target cells and induce transcription of approximately 20-30 genes in the target cells, and this results in an anti-viral state in the target cells.,48,1. INF Signaling,49,Types of Interferon,LPS: Lipopolysaccharide,脂多糖,50,IFN-a 的 抗 病 毒 作 用,病毒,病毒复制,抑制病 毒复制,信号转导,IFN-a,IFN-诱导蛋白,诱导刺激,胞核,胞核,Vir
21、al infection and replication introduces ssRNA, dsRNA and DNA:RNA hybrid byproducts. TLRsendosomes RNA helicasescytoplasm phosphorylation of TF type I interferon expression Secrete interferon,INF and INFR bind induction of genes： Cytokines chemokines apoptosis-related genes,51,Interferon pathway： Sec
22、retion、signaling and function,pDC,pDC： plasmacytoid dendritic cell 浆细胞样树突状细胞 TLR: toll-like receptors RNA helicases：RIG-1 and Mda-5 IRF：interferon regulatory factors 3, 5, 7 and 9 INFAR：interferon receptors,Interferon-inducible genes： 20-30 proteins Cytokines Chemokines apoptosis-related genes,These
23、 activities target viral protein synthesis, but also result in inhibition of host protein synthesis. It is important that these proteins are only made and activated when needed.,52,INF function,R,（medicine）,indirectly,directly,directly,53,Therapeutic Uses Of Interferons,54,常染色体隐性遗传性脑病，小头畸形，脑钙化,吸引白细胞
24、移行到感染部位。 多肽前体（包括信号肽）。 四个位置保守的半胱氨酸残基 形成两对双硫键,55,2. Chemokine Signaling,56,四类趋化因子,GPCR 四组，共19种。 CXCR ：6种 CCR： 11种 XCR ： 1种 CX3CR：1种,57,四类趋化因子受体,58,趋化因子及其受体,59,趋化因子的靶细胞,60,61,62,1 Regulation of AC 2 Regulation of PLC pathways 3 Ion channel regulation 4 Regulation of MAPK pathways 5 Regulation of PLA2 a
25、ctivity 6 cADPR,63,Intracellular signalling pathways activated by CCR,正常： 造血作用、淋巴组织发育、炎症反应、白细胞迁移、过敏、伤口修复、新血管生成、癌症发生和肿瘤迁移等。 异常： 多发性硬化症、类风湿关节炎、动脉硬化、哮喘和移植排斥等。,64,趋化因子的生理意义,65,趋化因子参与的疾病,牛皮癣,结节病,血管球性肾炎,骨关节炎,急性呼吸窘迫,哮喘,肺炎,风湿性关节炎,炎性肠病,脑膜炎,动脉粥样硬化,66,Figure 1 Disease targets of chemokine receptors and ligands
26、,Biochemical Society Transactions www.biochemsoctrans.org Biochem. Soc. Trans. (2004) 32, 366-377,过敏,特应性皮炎,肿瘤迁移,HIV lyses CD4+ T4 cells specifically, causing the profound immuno-suppression that is the hallmark of AIDS.,67,Chemokines and chemokine receptors: role in HIV infection,CD4+ T4 helper cell
27、s Natural Killer cells CD8+ Killer T cells Macrophages Dendritic cells Cells of the nervous system (oligodendrocytes, astrocytes, neurones, glial cells and brain macrophages),68,Cells that are infected by HIV,The outer domain of gp120 binds to the CD4 antigen. This leads to a conformational change i
28、n gp120 and a co-receptor binding site is exposed. This region of gp120 binds to the chemokine receptor. Binding to the chemokine receptor allows another conformational change to occur so that regions of the gp41 HIV protein interact to form a fusion domain that allows the viral and cell membrane to
29、 fuse. As a result the viral core enters the cytoplasm.,69,Chemokine receptor help HIV to enter a cell,Chemokine receptors are involved, in association with CD4 antigen, in infection by HIV (left). The chemokine can block attachment of the virus to its receptors (middle). Mutations in the chemokine
30、receptor can lead to resistance to HIV infection (right),70,Chemokines resist to HIV infection,Entry of HIV via the mucosal route and transit via dendritic cells to the lymph nodes,71,72,regulate immune cells induce apoptotic cell death induce inflammation inhibit tumorigenesis inhibit viral replica
31、tion,73,3. TNF Signaling,74,TNF,75,TNFR超家族成员的功能,76,77,CD95 (or Fas) DR4 DR5 TNFR1 DR3 (DR6?),78,Death receptors (DR),(FADD),(TRADD),DRs,TNFR,Receptor without DD,79,127 aa. 6 antiparallel, amphipathic alpha-helices,80,Death domain (DD),Fas DD,FADD：Fas-associated death domain protein,81,Adaptor,1.FADD
32、 2.TRADD,caspases 8 and 10（apoptosis-initiating proteases）,RIP1 （ DD-containing kinase ） TRAF2 （ E3 ubiquitin ligases ） cIAPs （ cellular inhibitor of apoptosis proteins ）,TRADD：TNF receptorassociated DD,TRAF2：TNF receptorassociated factor 2,RIP1：receptor-interacting protein-1,82,83,FADD-mediated DR
33、signaling,DISC： death-inducing signaling complex,autocatalytic processing,T cells,B cells,Bcl-2family protein,84,TRADD-mediated DR signaling,1.Proinflammatory cytokines 2.Chemokines 3.Antiapoptotic factors （cIAPs, c-FLIP）,1.Proliferation 2.Differentiation 3.Inflammation 4.Apoptosis.,polyubiquitinati
34、on of RIP1,cIAPs,85,Complex I,Complex II,Cross-talk between DR signaling adaptors,86,To Die? Or To live?,Model of TNFR1-Mediated Apoptosis,If NF-kB activation triggered by complex I is successful, cellular FLIP levels are sufficiently elevated to block apoptosis and cells survive.,87,Some TNFR famil
35、y members do not signal, but act as decoys that compete with receptors for ligands. Decoy receptors overexpress in tumor. Kill cancer cells: 1. activate death-receptor signalling 2. antibodies or small molecules (antagonize decoy receptors),88,Decoy receptors,89,NGFR signal pathway,白细胞介素（interleukin
36、) 1979年开始命名，发现于白细胞（Leukocytes）。 实际上，淋巴细胞、单核细胞或其它非单核细胞也可以产生。 在细胞间相互作用、免疫调节、造血以及炎症过程中起重要调节作用。 IL-1 IL-23。,90,4.IL Signaling,91,Other：src 激酶、 PI3, Pyk2 和Bcl2 蛋白,EPO, erythropoietin; G-CSF, granulocyte colony-stimulating factor; IFN, interferon; IL, interleukin; LIF, Leukemia inhibitory factor; OSM, onc
37、ostatin M; Th, T helper.,92,Yoshimura et al. Arthritis Research & Therapy 2005 7:100 doi:10.1186/ar1741,一、细胞因子导论 二、细胞因子参与的信号通路 三、几个重要细胞因子及其信号通路,93,目录,细胞因子的产生 细胞因子的命名 细胞因子发挥作用的三种方式 细胞因子的共同特点 细胞因子的生物学效应 细胞因子受体,94,一、细胞因子导论,JAK-STATS MAPK（ERK、JNK、p38） NF-kB Apoptosis GPCR,95,二、细胞因子参与的信号通路,1. INF Signaling 2. Chemokine Signaling 3. TNF Signaling 4. IL Signaling,96,三、几个重要细胞因子及其信号通路,