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21217011
NF-κB1 inhibits TLR-induced IFN-β production in macrophages through TPL-2-dependent ERK activation.

J Immunol, 2011/2/15;186(4):1989-96.

Yang HT[1], Wang Y, Zhao X, Demissie E, Papoutsopoulou S, Mambole A, O'Garra A, Tomczak MF, Erdman SE, Fox JG, Ley SC, Horwitz BH

Affiliations

PMID: 21217011DOI: 10.4049/jimmunol.1001003

Impact factor: 5.426

Abstract
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.
MeSH terms
Animals; Bone Marrow Cells; Cells, Cultured; Enzyme Activation; Gene Expression Profiling; Interferon-beta; MAP Kinase Kinase Kinases; Macrophages; Male; Mice; Mice, 129 Strain; Mice, Inbred C57BL; Mice, Knockout; Mitogen-Activated Protein Kinase 3; NF-kappa B p50 Subunit; Proto-Oncogene Proteins; Toll-Like Receptors
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