1. NF-κB1 Inhibits TLR-Induced IFN-β Production in Macrophages through TPL-2–Dependent ERK Activation
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James G. Fox, Stamatia Papoutsopoulou, Susan E. Erdman, Michal Tomczak, Steven C. Ley, Anne O'Garra, Huei-Ting Yang, Ezana Demissie, Yan Yan Wang, Xixing Zhao, Agnes Mambole, Bruce H. Horwitz, Massachusetts Institute of Technology. Department of Biological Engineering, Massachusetts Institute of Technology. Division of Comparative Medicine, Fox, James G., and Erdman, Susan E.
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Male ,MAPK/ERK pathway ,Mice, 129 Strain ,Mitogen-Activated Protein Kinase 3 ,Immunology ,Bone Marrow Cells ,Biology ,Article ,Mice ,Proto-Oncogene Proteins ,Gene expression ,Animals ,Immunology and Allergy ,Protein kinase A ,Autocrine signalling ,Cells, Cultured ,Mice, Knockout ,MAP kinase kinase kinase ,Kinase ,Gene Expression Profiling ,Macrophages ,Toll-Like Receptors ,NF-kappa B p50 Subunit ,Interferon-beta ,MAP Kinase Kinase Kinases ,Molecular biology ,Enzyme Activation ,Mice, Inbred C57BL ,Phosphorylation - Abstract
available in PMC 2012 February 15., 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., National Institutes of Health (U.S.) (NIH AI52267), National Institutes of Health (U.S.) (NIH CA108854), National Institutes of Health (U.S.) (NIH CA67529), Medical Research Council (Great Britain)
- Published
- 2011
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