NOS1-derived nitric oxide promotes NF-κB transcriptional activity through inhibition of suppressor of cytokine signaling-1

摘要: The NF-κB pathway is central to the regulation of inflammation. Here, we demonstrate that low-output nitric oxide (NO) synthase 1 (NOS1 or nNOS) plays a critical role in inflammatory response by promoting activity NF-κB. Specifically, NOS1-derived NO production macrophages leads proteolysis suppressor cytokine signaling (SOCS1), alleviating its repression transcriptional activity. As result, NOS1−/− mice reduced production, lung injury, and mortality when subjected two different models sepsis. Isolated similar defects proinflammatory transcription on challenge with Gram-negative bacterial LPS. Consistently, found activated contain increased SOCS1 protein decreased levels p65 compared wild-type cells. NOS1-dependent S-nitrosation impairs binding targets for proteolysis. Treatment cells exogenous rescues both degradation stabilization protein. Point mutation analysis demonstrated Cys147 Cys179 are required NO-dependent degradation. These findings fundamental regulating TLR4-mediated gene transcription, as well intensity duration resulting host immune response.