Open AccessIRAK1BP1 inhibits inflammation by promoting nuclear translocation of NF-κB p50
Author(s) -
James Conner,
I. Smirnova,
Annie P. Moseman,
Alexander Poltorak
Publication year - 2010
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.011
H-Index - 771
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.1006894107
Subject(s) - p50 , innate immune system , inflammation , transcription factor , microbiology and biotechnology , biology , proinflammatory cytokine , nf κb , nfkb1 , cytokine , signal transduction , immune system , receptor , immunology , genetics , gene
An orchestrated balance of pro- and antiinflammatory cytokine release is critical for an innate immune response sufficient for pathogen defense without excessive detriment to host tissues. By using an unbiased forward genetic approach, we previously reported that IL-1R–associated kinase 1 binding protein 1 (IRAK1BP1) down-modulates Toll-like receptor-mediated transcription of several proinflammatory cytokines. To gain insights into the physiological relevance of the inhibitory role of IRAK1BP1 in inflammation, we generated mutant mice lacking IRAK1BP1. Here we report that IRAK1BP1 does not inhibit signaling pathways generally but rather changes the transcriptional profile of activated cells, leading to an increase in IL-10 production and promoting LPS tolerance. This shift in cytokine transcription correlates with an increased ratio of functional NF-κB subunit dimers comprised of p50/p50 homodimers relative to p50/p65 heterodimers. The increase in nuclear p50/p50 was consistent with the ability of IRAK1BP1 to bind to the p50 precursor molecule and IκB family member p105. We conclude that IRAK1BP1 functions through its effects on NF-κB as a molecular switch to bias innate immune pathways toward the resolution of inflammation.