| First Author | Yang HT | Year | 2011 |
| Journal | J Immunol | Volume | 186 |
| Issue | 4 | Pages | 1989-96 |
| PubMed ID | 21217011 | Mgi Jnum | J:169175 |
| Mgi Id | MGI:4939976 | Doi | 10.4049/jimmunol.1001003 |
| Citation | Yang HT, et al. (2011) NF-(kappa)B1 inhibits TLR-induced IFN-(beta) production in macrophages through TPL-2-dependent ERK activation. J Immunol 186(4):1989-96 |
| abstractText | Although NF-kappaB1 p50/p105 has critical roles in immunity, the mechanism by which NF-kappaB1 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-beta 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-beta production. Markedly higher serum levels of IFN-beta were observed in Nfkb1(-/-) mice than in wild-type mice following LPS injection, demonstrating that Nfkb1 inhibits IFN-beta 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-beta 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-beta secretion. Expression of the C-terminal ankyrin repeat domain of p105 in Nfkb1(-/-) macrophages, which rescued LPS activation of ERK, also inhibited IFN-beta expression. These data indicate that p50/p105 negatively regulates LPS-induced IFN signaling in macrophages by stabilizing TPL-2, thereby facilitating activation of ERK. |
