Divergence of apoptosis-inducing and preventing signals in bacteria-faced macrophages through myeloid differentiation factor 88 and IL-1 receptor-associated kinase members.
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-kappa B in macrophages, which suppresses NF-kappa B-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-kappa B 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-kappa B cascade. The distinct functions of IRAK members in macrophage survival were reflected by opposing effects of dominant-negative IRAK1 and IRAK2 on Y. 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.
Ruckdeschel
Klaus
K
Max von Pettenkofer Institute for Hygiene and Medical Microbiology, Munich, Germany. ruckdeschel@m3401.mpk.med.uni-muenchen.de
Mannel
Oliver
O
Schröttner
Percy
P
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D000943:Antigens, Differentiation / Q000502:physiology*; D017209:Apoptosis; D001426:Bacterial Proteins / Q000494:pharmacology; D002352:Carrier Proteins / Q000502:physiology; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases / Q000502:physiology; D002460:Cell Line; D002470:Cell Survival; D002478:Cells, Cultured; D003546:Cysteine Endopeptidases; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D053200:Fas-Associated Death Domain Protein; D053592:Interleukin-1 Receptor-Associated Kinases; D007976:Leupeptins / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000166:cytology / Q000276:immunology / Q000382:microbiology*; D051379:Mice; D008954:Models, Biological; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex; D011494:Protein Kinases / Q000502:physiology*; D011506:Proteins / Q000378:metabolism; D011971:Receptors, Immunologic / Q000502:physiology*; D015398:Signal Transduction; D048029:TNF Receptor-Associated Factor 6; D015008:Yersinia enterocolitica / Q000472:pathogenicity*
D048868:Adaptor Proteins, Signal Transducing; D000943:Antigens, Differentiation; D001426:Bacterial Proteins; D002352:Carrier Proteins; D015853:Cysteine Proteinase Inhibitors; C505534:Fadd protein, mouse; D053200:Fas-Associated Death Domain Protein; D007976:Leupeptins; D008070:Lipopolysaccharides; D009097:Multienzyme Complexes; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B; D011506:Proteins; D011971:Receptors, Immunologic; D048029:TNF Receptor-Associated Factor 6; C109227:YopP protein, Yersinia; D011494:Protein Kinases; D053592:Interleukin-1 Receptor-Associated Kinases; C507769:Irak1 protein, mouse; C505526:Casp8 protein, mouse; C506434:Casp9 protein, mouse; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde