Fas(CD95) induces macrophage proinflammatory chemokine production via a MyD88-dependent, caspase-independent pathway
Fas(CD95) induces macrophage proinflammatory chemokine production via a MyD88-dependent, caspase-independent pathway
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DOI：
10.1189/jlb.1006652
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发表时间：
2007-09-01
影响因子：
5.5
通讯作者：
Liles, W. Conrad
中科院分区：
文献类型：
--
作者：
Altemeier, William A.;Zhu, Xiaodong;Liles, W. Conrad
原型死亡受体Fas（CD 95）的激活可诱导半胱天冬酶依赖性细胞死亡和促炎趋化因子的产生，导致中性粒细胞募集和终末器官损伤。Fas上调趋化因子产生和释放的确切机制目前尚不清楚。我们假设Fas诱导的巨噬细胞释放趋化因子依赖于MyD 88衔接分子，而不依赖于caspase活性。为了验证这一假设，我们测量了在具有RNAi减弱的MyD 88表达的RAW 264.7细胞和MyD 88缺陷的原代巨噬细胞中趋化因子对Fas活化的响应。我们发现Fas诱导的趋化因子释放在MyD 88不存在的情况下被废除。在体内，MyD 88（-/-）小鼠有受损的CXCL 1/KC释放和多形核细胞募集响应Fas激活的单克隆抗体，Jo-2的治疗。此外，Fas诱导的趋化因子释放不依赖于IL-1受体信号传导或半胱天冬酶活性。我们的结论是MyD 88在Fas诱导的巨噬细胞介导的炎症中起着不可或缺的作用。
Activation of the prototypical death receptor, Fas (CD95), can induce both caspase-dependent cell death and production of proinflammatory chemokines, leading to neutrophil recruitment and end-organ injury. The precise mechanism(s) by which Fas up-regulates chemokine production and release, is currently unclear. We hypothesized that Fas-induced chemokine release by macrophages is dependent on the MyD88 adaptor molecule and independent of caspase activity. To test this hypothesis, we measured chemokine response to Fas activation both in RAW 264.7 cells with RNAi-attenuated MyD88 expression and in MyD88-deficient primary macrophages. We found that Fas-induced chemokine release was abrogated in the absence of MyD88. In vivo, MyD88(-/-) mice had impaired CXCL1/KC release and polymorphonuclear cell recruitment in response to intratracheal treatment with the Fas-activating monoclonal antibody, Jo-2. Furthermore, Fas-induced chemokine release was not dependent on either IL-1 receptor signaling or on caspase activity. We conclude that MyD88 plays an integral role in Fas-induced macrophage-mediated inflammation.