title: NF-κB1 inhibits TLR-induced IFN-β production in macrophages through TPL-2-dependent ERK activation.
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.
authors.affiliation: Division of Immune Cell Biology, National Institute for Medical Research, London, United Kingdom.
authors.forename: Huei-Ting
authors.initials: HT
authors.lastname: Yang
authors.forename: Yanyan
authors.initials: Y
authors.lastname: Wang
authors.forename: Xixing
authors.initials: X
authors.lastname: Zhao
authors.forename: Ezana
authors.initials: E
authors.lastname: Demissie
authors.forename: Stamatia
authors.initials: S
authors.lastname: Papoutsopoulou
authors.forename: Agnes
authors.initials: A
authors.lastname: Mambole
authors.forename: Anne
authors.initials: A
authors.lastname: O'Garra
authors.forename: Michal F
authors.initials: MF
authors.lastname: Tomczak
authors.forename: Susan E
authors.initials: SE
authors.lastname: Erdman
authors.forename: James G
authors.initials: JG
authors.lastname: Fox
authors.forename: Steven C
authors.initials: SC
authors.lastname: Ley
authors.forename: Bruce H
authors.initials: BH
authors.lastname: Horwitz
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000201:enzymology / Q000276:immunology / Q000378:metabolism; D002478:Cells, Cultured; D004789:Enzyme Activation / Q000235:genetics / Q000276:immunology; D020869:Gene Expression Profiling; D016899:Interferon-beta / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D020930:MAP Kinase Kinase Kinases / Q000502:physiology*; D008264:Macrophages / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism*; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism* / Q000502:physiology; D052002:NF-kappa B p50 Subunit / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D051193:Toll-Like Receptors / Q000037:antagonists & inhibitors / Q000502:physiology*
chemical_list: D052002:NF-kappa B p50 Subunit; C489548:NFKB1 protein, human; D011518:Proto-Oncogene Proteins; D051193:Toll-Like Receptors; C073701:Nfkb1 protein, mouse; D016899:Interferon-beta; D048052:Mitogen-Activated Protein Kinase 3; D020930:MAP Kinase Kinase Kinases; C489843:Map3k8 protein, mouse