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PMID: 17000866 Published · ppublish English Comparative Study Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

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

The Journal of experimental medicine ·Vol. 203 ·No. 10 ·2006-10-02 ·Pages 2377-89

Nakahira K, Kim HP, Geng XH, Nakao A, Wang X, Murase N, Drain PF, Wang X, Sasidhar M, Nabel EG, Takahashi T, Lukacs NW, Ryter SW, Morita K, Choi AM

Abstract

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 gp91(phox)-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 gp91(phox)-deficient macrophages, also indicating a role for NADPH oxidase. CO attenuated LPS-induced NADPH oxidase activity in vitro, potentially by binding to gp91(phox). Thus, CO negatively controlled TLR signaling pathways by inhibiting translocation of TLR to lipid rafts through suppression of NADPH oxidase-dependent ROS generation.

MeSH Terms
Animals Carbon Monoxide/toxicity DNA Primers Electrophoretic Mobility Shift Assay Heme Oxygenase-1/metabolism Immunoblotting Immunoprecipitation Macrophages/metabolism Membrane Microdomains/metabolism Mice Mice, Inbred C57BL Microscopy, Fluorescence Protein Transport/drug effects Reactive Oxygen Species/metabolism Reverse Transcriptase Polymerase Chain Reaction Signal Transduction/drug effects,physiology Toll-Like Receptors/metabolism
Chemicals
DNA Primers Reactive Oxygen Species Toll-Like Receptors Carbon Monoxide Heme Oxygenase-1
Authors & Affiliations
15 authors, click to expand affiliations / ORCID
Nakahira Kiichi
Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
Kim Hong Pyo
Geng Xue Hui
Nakao Atsunori
Wang Xue
Murase Noriko
Drain Peter F
Wang Xiaomei
Sasidhar Madhu
Nabel Elizabeth G
Takahashi Toru
Lukacs Nicholas W
Ryter Stefan W
Morita Kiyoshi
Choi Augustine M K
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Article Info
Journal
The Journal of experimental medicine
Abbr.
J Exp Med
ISSN
0022-1007
DOI
10.1084/jem.20060845
Published
2006-10-02
Epub
2006-00-25
Pages
2377-89
Language
English
Region
United States
NLM ID
2985109R
PMCID
PMC2118097
Subset
IM
Grants
NHLBI NIH HHS · P01HL070807 · United States
NHLBI NIH HHS · P01 HL070807 · United States
NHLBI NIH HHS · R01HL079904 · United States
NHLBI NIH HHS · R01HL055330 · United States
NHLBI NIH HHS · R01 HL060234 · United States
NHLBI NIH HHS · R01HL060234 · United States
NHLBI NIH HHS · R01 HL055330 · United States
NHLBI NIH HHS · R01 HL079904 · United States
External Links
PubMed source DOI: 10.1084/jem.20060845 PMC Full Text View journal details
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