The Fas-associated death domain protein suppresses activation of NF-kappa B by LPS and IL-1 beta

• Published in: The Journal of clinical investigation Vol. 109; no. 3; pp. 419 - 425
• Main Authors: Bannerman, Douglas D, Tupper, Joan C, Kelly, James D, Winn, Robert K, Harlan, John M
• Format: Journal Article
• Language: English
• Published: United States 01.02.2002
• Subjects: Adaptor Proteins, Signal Transducing; Animals; Carrier Proteins - genetics; Carrier Proteins - metabolism; Cell Line; Chemokine CXCL1; Chemokines, CXC; Chemotactic Factors - biosynthesis; DNA-Binding Proteins - metabolism; Fas ligand; Fas-Associated Death Domain Protein; Gene Expression; Growth Substances - biosynthesis; Humans; I-kappa B Proteins; I^KB protein; Intercellular Signaling Peptides and Proteins; Interleukin-1 - pharmacology; Interleukin-6 - biosynthesis; IRAK protein; Lipopolysaccharides - pharmacology; Mice; Mice, Knockout; MyD88 protein; NF-kappa B - metabolism; NF-KappaB Inhibitor alpha; Transfection
• ISSN: 0021-9738
• DOI: 10.1172/JCI0214774

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.