IRAK1BP1 inhibits inflammation by promoting nuclear translocation of NF-kappaB p50.
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-kappaB 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 IkappaB family member p105. We conclude that IRAK1BP1 functions through its effects on NF-kappaB as a molecular switch to bias innate immune pathways toward the resolution of inflammation.
Graduate Program in Immunology, Tufts University Sackler School of Biomedical Sciences, Boston, MA 02111, USA.
James R
JR
Conner
Irina I
II
Smirnova
Annie Park
AP
Moseman
Alexander
A
Poltorak
D021581:Active Transport, Cell Nucleus; D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism*; D019281:Dimerization; D015971:Gene Expression Regulation, Enzymologic; D007113:Immunity, Innate; D007249:Inflammation; D016753:Interleukin-10 / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins; D008070:Lipopolysaccharides / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D052002:NF-kappa B p50 Subunit / Q000378:metabolism*; D015398:Signal Transduction; D051193:Toll-Like Receptors / Q000378:metabolism
D002352:Carrier Proteins; D015850:Interleukin-6; D047908:Intracellular Signaling Peptides and Proteins; D008070:Lipopolysaccharides; D052002:NF-kappa B p50 Subunit; C493527:SIMPL protein, mouse; D051193:Toll-Like Receptors; D016753:Interleukin-10