NF-κB1 Inhibits TLR-Induced IFN-β Production in Macrophages Through TPL-2-dependent ERK Activation
Author(s)Yang, Huei-Ting; Wang, Yanyan; Zhao, Xixing; Demissie, Ezana; Papoutsopoulou, Stamatia; Mambole, Agnes; O’Garra, Anne; Tomczak, Michal F.; Erdman, Susan E.; Fox, James G.; Ley, Steven C.; Horwitz, Bruce H.; ... Show more Show less
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Although NF-κB1 p50/p105 has critical roles in immunity, the mechanism by which NF-κB1 regulates inflammatory responses is unclear. In this study, we analyzed the gene expression profile of LPS-stimulated Nfkb1−/− macrophages that lack both p50 and p105. Deficiency of p50/p105 selectively increased the expression of IFN-responsive genes, which correlated with increased IFN-β expression and STAT1 phosphorylation. IFN Ab-blocking experiments indicated that increased STAT1 phosphorylation and expression of IFN-responsive genes observed in the absence of p50/p105 depended upon autocrine IFN-β production. Markedly higher serum levels of IFN-β were observed in Nfkb1−/− mice than in wild-type mice following LPS injection, demonstrating that Nfkb1 inhibits IFN-β production under physiological conditions. TPL-2, a mitogen-activated protein kinase kinase kinase stabilized by association with the C-terminal ankyrin repeat domain of p105, negatively regulates LPS-induced IFN-β production by macrophages via activation of ERK MAPK. Retroviral expression of TPL-2 in Nfkb1−/− macrophages, which are deficient in endogenous TPL-2, reduced LPS-induced IFN-β secretion. Expression of the C-terminal ankyrin repeat domain of p105 in Nfkb1−/− macrophages, which rescued LPS activation of ERK, also inhibited IFN-β expression. These data indicate that p50/p105 negatively regulates LPS-induced IFN signaling in macrophages by stabilizing TPL-2, thereby facilitating activation of ERK.
available in PMC 2012 February 15.
DepartmentMassachusetts Institute of Technology. Department of Biological Engineering; Massachusetts Institute of Technology. Division of Comparative Medicine
Journal of Immunology
American Association of Immunologists
Yang, H.-T. et al. “NF- B1 Inhibits TLR-Induced IFN- Production in Macrophages Through TPL-2-Dependent ERK Activation.” The Journal of Immunology 186.4 (2011): 1989–1996. Web.
Author's final manuscript