NF-κB1 Inhibits TLR-Induced IFN-β Production in Macrophages Through TPL-2-dependent ERK Activation1

Although NF-κB1 p50/p105 has critical roles in immunity, the mechanism by which NF-κB1 regulates inflammatory responses is unclear. Here, we analyzed the gene expression profile of lipopolysaccharide (LPS)-stimulated Nfkb1 −/− macrophages that lack both p50 and p105. Deficiency of p50/p105 selectively increased the expression of interferon (IFN)-responsive genes, which correlated with increased IFN-β expression and STAT1 phosphorylation. Interferon antibody blocking experiments indicated that increased STAT1 phosphorylation and expression of interferon-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 WT 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 interferon-β production by macrophages via activation of ERK MAP kinase. Retroviral expression of TPL-2 in Nfkb1 −/− macrophages, which are deficient in endogenous TPL-2, reduced LPS-induced interferon-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 interferon-signaling in macrophages by stabilizing TPL-2, thereby facilitating activation of ERK.