The Journal of Experimental Medicine
Torrey Pines Biolabs
  Home | Help | Feedback | Subscriptions | Archive | Search | Table of Contents
Published online 25 September 2006 doi:10.1084/jem.20060845
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 203, Number 10, 2377-2389
This Article
Right arrow Full Text
Right arrow Full Text (PDF, 4543K)
Right arrow PPT slides of all figures
Right arrow Supplemental Material Index
Right arrow Alert me when this article is cited
Right arrow Citation Map
Services
Right arrow Email this article
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new content in the JEM
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via CrossRef
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Nakahira, K.
Right arrow Articles by Choi, A. M.K.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Nakahira, K.
Right arrow Articles by Choi, A. M.K.
Social Bookmarking
Add to CiteULike   Add to Complore   Add to Connotea   Add to Del.icio.us   Add to Digg   Add to Reddit   Add to Technorati  
What's this?

ARTICLE

 Carbon monoxide differentially inhibits TLR signaling pathways by regulating ROS-induced trafficking of TLRs to lipid rafts

Kiichi Nakahira1, Hong Pyo Kim1, Xue Hui Geng2, Atsunori Nakao3, Xue Wang1, Noriko Murase3, Peter F. Drain2, Xiaomei Wang1, Madhu Sasidhar4, Elizabeth G. Nabel5, Toru Takahashi6, Nicholas W. Lukacs7, Stefan W. Ryter1, Kiyoshi Morita6, and Augustine M.K. Choi1

1 Division of Pulmonary, Allergy and Critical Care Medicine, 2 Department of Cell Biology and Physiology, and 3 Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213
4 Section of Pulmonary and Critical Care Medicine, Yale University School of Medicine, New Haven, CT 06520
5 National Heart, Lung, and Blood Institute, National Institutes of Health (NIH), Bethesda, MD 20892
6 Department of Anesthesiology and Resuscitology, Okayama University Medical School, Okayama-shi 700-8558, Japan
7 Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109

CORRESPONDENCE Augustine M.K. Choi: choiam{at}upmc.edu

Carbon monoxide (CO), a byproduct of heme catabolism by heme oxygenase (HO), confers potent antiinflammatory effects. Here we demonstrate that CO derived from HO-1 inhibited Toll-like receptor (TLR) 2, 4, 5, and 9 signaling, but not TLR3-dependent signaling, in macrophages. Ligand-mediated receptor trafficking to lipid rafts represents an early event in signal initiation of immune cells. Trafficking of TLR4 to lipid rafts in response to LPS was reactive oxygen species (ROS) dependent because it was inhibited by diphenylene iodonium, an inhibitor of NADPH oxidase, and in gp91phox-deficient macrophages. CO selectively inhibited ligand-induced recruitment of TLR4 to lipid rafts, which was also associated with the inhibition of ligand-induced ROS production in macrophages. TLR3 did not translocate to lipid rafts by polyinosine-polycytidylic acid (poly(I:C)). CO had no effect on poly(I:C)-induced ROS production and TLR3 signaling. The inhibitory effect of CO on TLR-induced cytokine production was abolished in gp91phox-deficient macrophages, also indicating a role for NADPH oxidase. CO attenuated LPS-induced NADPH oxidase activity in vitro, potentially by binding to gp91phox. Thus, CO negatively controlled TLR signaling pathways by inhibiting translocation of TLR to lipid rafts through suppression of NADPH oxidase–dependent ROS generation.

Abbreviations used: CO, carbon monoxide; CTx, cholera toxin; DPI, diphenylene iodonium; GM1, glycosphingolipid 1; HO, heme oxygenase; IP-10, IFN-{gamma}–inducible protein 10; IRF-3, IFN regulatory factor 3; MAPK, mitogen-activated protein kinase; MßCD, methyl-ß-cyclodextrin; MDC, monodansylcadaverine; NAC, N-acetyl-L-cysteine; PAMP, pathogen-associated molecular pattern; poly(I:C), polyinosine-polycytidylic acid; RANTES, regulated upon activation, normal T expressed, and presumably secreted; ROS, reactive oxygen species; TLR, Toll-like receptor; TRAF, TNF receptor–associated factor; TRIF, TIR domain–containing adaptor-inducing IFN-ß.

K. Nakahira and H.P. Kim contributed equally to this work.


Add to CiteULike CiteULike   Add to Complore Complore   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us   Add to Digg Digg   Add to Reddit Reddit   Add to Technorati Technorati    What's this?


This article has been cited by other articles:



  Home | Help | Feedback | Subscriptions | Archive | Search
TABLE OF CONTENTS