The Fas-associated death domain protein suppresses activation of NF-kappa B by LPS and IL-1 beta.
Activation of NF-kappa B by bacterial LPS promotes the upregulation of proinflammatory cytokines that contribute to the pathogenesis of Gram-negative septic shock. LPS activation of NF-kappa B is dependent upon the interaction of two death domain-containing (DD-containing) proteins, MyD88 and IL-1 receptor-associated kinase IRAK. Another DD-containing protein, Fas-associated death domain (FADD), also binds MyD88 through respective DD-DD interactions. Although FADD has been classically described as a proapoptotic signaling molecule, several reports have implicated a role for FADD in mediating NF-kappa B activation. In the present report, we investigated whether FADD could mediate LPS activation of NF-kappa B. Overexpression of FADD blocked LPS-induced NF-kappa B activation, whereas absence of FADD enhanced activation of NF-kappa B by LPS. Further, LPS-induced expression of two NF-kappa B-dependent gene products, IL-6 and KC, was enhanced in FADD(-/-) mouse embryo fibroblasts (MEFs) compared with wild-type. This increase in NF-kappa B activity correlated with enhanced I kappa B degradation. FADD(-/-) MEFs were also resistant to NF-kappa B activation induced by IL-1 beta. Finally, reconstitution of full-length FADD in the FADD(-/-) MEFs completely reversed the enhanced activation of NF-kappa B elicited by either LPS or IL-1 beta. Together, these data indicate that FADD negatively regulates LPS- and IL-1 beta-induced NF-kappa B activation and that this regulation occurs upstream of I kappa B degradation.
Bannerman
Douglas D
DD
Department of Surgery, University of Washington School of Medicine, Seattle, Washington, USA. dbannerm@u.washington.edu
Tupper
Joan C
JC
Kelly
James D
JD
Winn
Robert K
RK
Harlan
John M
JM
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D054360:Chemokine CXCL1; D019743:Chemokines, CXC; D002630:Chemotactic Factors / Q000096:biosynthesis; D004268:DNA-Binding Proteins / Q000378:metabolism; D053200:Fas-Associated Death Domain Protein; D015870:Gene Expression; D006133:Growth Substances / Q000096:biosynthesis; D006801:Humans; D020672:I-kappa B Proteins; D036341:Intercellular Signaling Peptides and Proteins; D007375:Interleukin-1 / Q000494:pharmacology*; D015850:Interleukin-6 / Q000096:biosynthesis; D008070:Lipopolysaccharides / Q000494:pharmacology*; D051379:Mice; D018345:Mice, Knockout; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism*; D014162:Transfection
D048868:Adaptor Proteins, Signal Transducing; C475829:CXCL1 protein, human; D002352:Carrier Proteins; D054360:Chemokine CXCL1; D019743:Chemokines, CXC; D002630:Chemotactic Factors; C475895:Cxcl1 protein, mouse; D004268:DNA-Binding Proteins; C505533:FADD protein, human; C505534:Fadd protein, mouse; D053200:Fas-Associated Death Domain Protein; D006133:Growth Substances; C083487:I kappa B beta protein; D020672:I-kappa B Proteins; D036341:Intercellular Signaling Peptides and Proteins; D007375:Interleukin-1; D015850:Interleukin-6; D008070:Lipopolysaccharides; D016328:NF-kappa B; C000606204:NFKBIA protein, human; C000606205:Nfkbia protein, mouse; D000072000:NF-KappaB Inhibitor alpha