Intragraft TNF Receptor Signaling Contributes to Activation of Innate and Adaptive Immunity in a Renal Allograft Model
Intragraft TNF Receptor Signaling Contributes to Activation of Innate and Adaptive Immunity in a Renal Allograft Model
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DOI：
10.1097/tp.0b013e3181938971
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发表时间：
2009-01-27
期刊：
影响因子：
6.2
通讯作者：
Abecassis, Michael
中科院分区：
文献类型：
--
作者：
Hummel, Mary;Kurian, Sunil M.;Abecassis, Michael
背景资料。肿瘤坏死因子水平升高是同种异体移植排斥反应的危险因素。体外研究表明，肿瘤坏死因子与其受体的结合激活了信号级联反应，从而诱导了许多与炎症有关的基因的表达。移植物内肿瘤坏死因子受体(TNFR)信号在同种异体移植物基因表达激活中的作用尚未被研究。通过基因表达谱分析和实时定量聚合酶链式反应分析，研究TNFR信号在移植肾移植后2天移植肾细胞基因表达早期激活中的作用。肿瘤坏死因子受体在激活转录因子在移植物内的表达中起关键作用，这些转录因子控制天然和获得性免疫以及应激反应(干扰素调节因子[IRF]1、IRF 8、Isgf3g和ATF3)、介导炎症的细胞因子和受体(肿瘤坏死因子、白介素[IL]-6、干扰素-γ、抑癌素M受体[OMCR]、Toll样受体[TLR]2和IL-2Rγ)、募集炎症细胞的趋化因子和黏附分子(Cxcl9、Cxcl11、E-选择素和细胞内黏附分子[ICAM]-1)、参与T细胞共刺激和抗原的处理和呈递的基因(H2-DMB、Psmb8、Psmb8、Psmb8)。和CD40)，以及调节干扰素反应的基因。除促炎作用外，TNFR信号还可诱导SOCS3的表达，SOCS3是IL-6、OSMR信号和Nfkbie的负调节因子，也是TNFR信号转导的负调节因子。这些研究阐明了肿瘤坏死因子在免疫反应的激活和下调中的多效性作用，以及在同种异体移植早期反应中TNFR与其他细胞因子信号通路之间的复杂相互作用。
Background. Increased levels of tumor necrosis factor (TNF) are a risk factor for allograft rejection. In vitro studies have shown that binding of TNF to its receptor activates signaling cascades that induce expression of many genes involved in inflammation. The role of intragraft TNF receptor (TNFR) signaling in activation of gene expression in allografts has not been studied.Methods. Gene expression profiling and quantitative real-time polymerase chain reaction analysis were used to investigate the role of TNFR signaling in the early intragraft activation of cellular gene expression in renal allografts at 2 days posttransplant.Results. The TNFRs play a critical role in activating intragraft expression of transcription factors controlling innate and adaptive immunity and stress responses (interferon regulatory factor [IRF]1, IRF 8, Isgf3g, and ATF3) of cytokines and receptors mediating inflammation (TNF, interleukin [IL]-6, interferon-gamma, oncostatin M receptor [OMCR], toll-like receptor [TLR]2, and IL-2R gamma), of chemokines and adhesion molecules that recruit inflammatory cells (Cxcl9, Cxcl11, E-selectin, and intracellular adhesion molecule [ICAM]-1), of genes involved in costimulation of T cells and processing and presentation of antigens (H2-DMb, Psmb8, and CD40), and genes that mediate the response to interferons. In addition to its proinflammatory role, TNFR signaling induces expression of SOCS3, a negative regulator of IL-6 and OSMR signaling and Nfkbie, and a negative regulator of TNFR signal transduction.Conclusions. These studies illustrate the pleiotropic effect of TNF in both activation and down-modulation of the immune response and the complex interactions between the TNFRs and other cytokine signaling pathways in the early allograft response.