Regulation of MyD88-dependent signaling events by S nitrosylation retards toll-like receptor signal transduction and initiation of acute-phase immune responses.
Nitric oxide (NO) has been thought to regulate the immune system through S nitrosylation of the transcriptional factor NF-kappaB. However, regulatory effects of NO on innate immune responses are unclear. Here, we report that NO has a capability to control Toll-like receptor-mediated signaling through S nitrosylation. We found that the adaptor protein MyD88 was primarily S nitrosylated, depending on the presence of endothelial NO synthase (eNOS). S nitrosylation at a particular cysteine residue within the TIR domain of MyD88 resulted in slight reduction of the NF-kappaB-activating property. This modification could be restored by the antioxidant glutathione. Through S nitrosylation, NO could negatively regulate the multiple steps of MyD88 functioning, including translocation to the cell membrane after LPS stimulation, interaction with TIRAP, binding to TRAF6, and induction of IkappaBalpha phosphorylation. Interestingly, glutathione could reversely neutralize such NO-derived effects. We also found that an acute febrile response to LPS was precipitated in eNOS-deficient mice, indicating that eNOS-derived NO exerts an initial suppressive effect on inflammatory processes. Thus, NO has a potential to retard induction of MyD88-dependent signaling events through the reversible and oxidative modification by NO, by which precipitous signaling reactions are relieved. Such an effect may reflect appropriate regulation of the acute-phase inflammatory responses in living organisms.
Into
Takeshi
T
Section of Oral Infection Control, Department of Oral Disease Research, National Institute for Longevity Sciences, National Center for Geriatrics and Gerontology, 36-3 Gengo, Morioka, Obu, Aichi 474-8522, Japan. into@nils.go.jp
Inomata
Megumi
M
Nakashima
Misako
M
Shibata
Ken-Ichiro
K
Häcker
Hans
H
Matsushita
Kenji
K
D000210:Acute-Phase Reaction / Q000276:immunology*; D000818:Animals; D002460:Cell Line; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D053592:Interleukin-1 Receptor-Associated Kinases / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000201:enzymology / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism*; D000072000:NF-KappaB Inhibitor alpha; D009569:Nitric Oxide / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology*; D051193:Toll-Like Receptors / Q000276:immunology*
D020672:I-kappa B Proteins; D008070:Lipopolysaccharides; D053594:Myeloid Differentiation Factor 88; C000606204:NFKBIA protein, human; C000606205:Nfkbia protein, mouse; D051193:Toll-Like Receptors; D000072000:NF-KappaB Inhibitor alpha; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D053592:Interleukin-1 Receptor-Associated Kinases; D005978:Glutathione