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The Heme Oxygenase-1/Carbon Monoxide Pathway Suppresses TLR4 Signaling by Regulating the Interaction of TLR4 with Caveolin-1¹

Xiao Mei Wang^*, Hong Pyo Kim^*,, Kiichi Nakahira^*,, Stefan W. Ryter^*, and Augustine M. K. Choi^2,

^* Division of Pulmonary, Allergy and Critical Care Medicine, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15213; and Pulmonary and Critical Care Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115

Caveolin-1 (cav-1), the principle structural protein of plasmalemmal caveolae, regulates inflammatory signaling processes originating at the membrane. We show that cav-1 bound to TLR4 and inhibited LPS-induced proinflammatory cytokine (TNF- and IL-6) production in murine macrophages. Mutation analysis revealed a cav-1 binding motif in TLR4, essential for this interaction and for attenuation of proinflammatory signaling. Cav-1 was required for the anti-inflammatory effects of carbon monoxide (CO), a product of heme oxygenase-1 (HO-1) activity. CO augmented the cav-1/TLR4 interaction. Upon LPS stimulation, HO-1 trafficked to the caveolae by a p38 MAPK-dependent mechanism, where it down-regulated proinflammatory signaling. These results reveal an anti-inflammatory network involving cav-1 and HO-1.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by American Heart Association Awards AHA 0515312U (to X.M.W.), AHA 0335035N (to S.W.R.), and AHA 0525552U (to H.P.K.), and by Grants R01-HL60234, R01-HL55330, R01-HL079904, and P01-HL70807 from the National Institutes of Health (to A.M.K.C.).

² Address correspondence and reprint requests to Dr. Augustine M. K. Choi, Pulmonary and Critical Care Medicine, Brigham and Women’s Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115. E-mail address: amchoi{at}rics.bwh.harvard.edu

³ Abbreviations used in this paper: cav-1, caveolin-1; NOS, NO synthase; BVR, biliverdin reductase; CO, carbon monoxide; HO, heme oxygenase; TRIF, Toll/IL-1R domain-containing adaptor-inducing IFN-β; MKK3, MAPK kinase-3; siRNA, small interfering RNA; PKC, protein kinase C; ppm, parts per million.

⁴ The online version of this article contains supplemental material.

This article has been cited by other articles:

				S. W. Ryter and A. M. K. Choi Heme Oxygenase-1/Carbon Monoxide: From Metabolism to Molecular Therapy Am. J. Respir. Cell Mol. Biol., September 1, 2009; 41(3): 251 - 260. [Abstract] [Full Text] [PDF]