Divergence of apoptosis-inducing and preventing signals in bacteria-faced macrophages through myeloid differentiation factor 88 and IL-1 receptor-associated kinase members

被引:55
作者
Ruckdeschel, K [1 ]
Mannel, O [1 ]
Schröttner, P [1 ]
机构
[1] Pettenkofer Inst Hyg & Med Microbiol, D-80336 Munich, Germany
关键词
D O I
10.4049/jimmunol.168.9.4601
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
The induction of apoptosis in host cells is a common strategy by which pathogenic bacteria interfere with the host immune response. The Yersinia enterocolitica outer protein P (YopP) inhibits activation of transcription factor NF-kappaB in macrophages, which suppresses NF-kappaB-dependent antiapoptotic activities. The simultaneous initiation of proapoptotic signaling by yersiniae infection or LPS treatment results in macrophage apoptosis. In this study, we used YopP as a tool to dissect survival- and death-inducing pathways in bacteria-faced macrophages. We cotransfected J774A.1 macrophages with expression plasmids for YopP and dominant-negative mutants of signal transmitters of the NF-kappaB cascade downstream from the LPS receptor complex. Dominant-negative myeloid differentiation factor 88 (MyD88) or IL-1R-associated kinase (IRAK) 2 diminished LPS-induced apoptosis in YopP-transfected macrophages, suggesting implication of MyD88 and IRAK2 in signaling cell death. In contrast, dominant-negative IRAK1 and TNFR-associated factor 6 (TRAF6) did not provide protection, but augmented LPS-mediated apoptosis in the absence of YopP, which indicates roles of IRAK1 and TRAF6 in the antiapoptotic signal relay of the NF-kappaB cascade. The distinct functions of IRAK members in macrophage survival were reflected by opposing effects of dominant-negative TRAM and IRAK2 on 1: enterocolitica-mediated apoptosis. Yersiniae- and LPS-dependent cell death were substantially attenuated by a specific caspase-8 inhibitory peptide or by dominant negative Fas-associated death domain protein (FADD). This suggests, that Yersinia-induced apoptosis involves a proapoptotic signal relay through MyD88 and IRAK2, which potentially targets the Fas-associated death domain protein/caspase-8 apoptotic pathway, whereas IRAK1 and TRAF6 counteract the bacteria-induced cytotoxic response by signaling macrophage survival.
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收藏
页码:4601 / 4611
页数:11
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