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Molecular and Cellular Biology, February 2008, p. 1338-1347, Vol. 28, No. 4
0270-7306/08/$08.00+0     doi:10.1128/MCB.01412-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Regulation of MyD88-Dependent Signaling Events by S Nitrosylation Retards Toll-Like Receptor Signal Transduction and Initiation of Acute-Phase Immune Responses{triangledown}

Takeshi Into,1* Megumi Inomata,1 Misako Nakashima,1 Ken-ichiro Shibata,2 Hans Häcker,3 and Kenji Matsushita1

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,1 Laboratory of Oral Molecular Microbiology, Department of Oral Pathobiological Science, Hokkaido University Graduate School of Dental Medicine, Sapporo 060-8586, Japan,2 Department of Infectious Diseases, St. Jude Children's Research Hospital, 332 North Lauderdale Street, Memphis, Tennessee 381053

Received 7 August 2007/ Returned for modification 23 September 2007/ Accepted 28 November 2007

Nitric oxide (NO) has been thought to regulate the immune system through S nitrosylation of the transcriptional factor NF-{kappa}B. 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-{kappa}B-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 I{kappa}B{alpha} 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.

* Corresponding author. Mailing address: 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. Phone: 81-562-44-5651, ext. 5064. Fax: 81-562-46-8684. E-mail: into{at}nils.go.jp

{triangledown} Published ahead of print on 17 December 2007.

Molecular and Cellular Biology, February 2008, p. 1338-1347, Vol. 28, No. 4
0270-7306/08/$08.00+0     doi:10.1128/MCB.01412-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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