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J. Biol. Chem. 278 (39): 36993-36998

© 2003 by The American Society for Biochemistry and Molecular Biology, Inc.

Suppression of Inflammatory Cytokine Production by Carbon Monoxide Involves the JNK Pathway and AP-1*

Danielle Morse {ddagger}, Soeren E. Pischke {ddagger} ||, Zhihong Zhou {ddagger}, Roger J. Davis §, Richard A. Flavell ¶, Torsten Loop ||, Sherrie L. Otterbein {ddagger}, Leo E. Otterbein {ddagger} **, and Augustine M. K. Choi {ddagger} {ddagger}{ddagger}

{ddagger}Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213, the §Howard Hughes Medical Institute and Program in Molecular Medicine, Department of Biochemistry and Molecular Biology, University of Massachusetts Medical School, Worcester, Massachusetts 01605, the Howard Hughes Medical Institute and Section of Immunobiology, Yale University School of Medicine, New Haven, Connecticut 06520, and the ||Department of Anesthesia, University Hospital, Freiburg D-79098, Germany

Abstract: The stress-inducible protein heme oxygenase-1 provides protection against oxidative stress and modulates pro-inflammatory cytokines. As the sepsis syndrome results from the release of pro-inflammatory mediators, we postulated that heme oxygenase-1 and its enzymatic product CO would protect against lethality in a murine model of sepsis. Mice treated with a lethal dose of lipopolysaccharide (LPS) and subsequently exposed to inhaled CO had significantly better survival and lower serum interleukin (IL)-6 and IL-1{beta} levels than their untreated counterparts. In vitro, mouse macrophages exposed to LPS and CO had significantly attenuated IL-6 production; this effect was concentration-dependent and occurred at a transcriptional level. The same effect was seen with increased endogenous CO production through overexpression of heme oxygenase-1. Mutation within the AP-1-binding site in the IL-6 promoter diminished the effect of CO on promoter activity, and treatment of macrophages with CO decreased AP-1 binding in an electrophoretic mobility shift assay. Electrophoretic mobility supershift assay indicated that the JunB, JunD, and c-Fos components of AP-1 were particularly affected. Upstream of AP-1, CO decreased JNK phosphorylation in murine macrophages and lung endothelial cells. Mice deficient in the JNK pathway had decreased serum levels of IL-6 and IL-1{beta} in response to LPS compared with control mice, and no effect of CO on these cytokine levels was seen in Jnk1 or Jnk2 genedeleted mice. In summary, these results suggest that CO provides protection in a murine model of sepsis through modulation of inflammatory cytokine production. For the first time, the effect of CO is shown to be mediated via the JNK signaling pathway and the transcription factor AP-1.

Received for publication March 21, 2003. Revision received July 5, 2003.

* 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.

** Supported by an American Heart Association grant-in-aid.

{ddagger}{ddagger} Supported in part by National Institutes of Health Grants HL60234, HL55330, and AI42365. To whom correspondence should be addressed: Div. of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh School of Medicine, NW 628 UPMC Montefiore, 3459 Fifth Ave., Pittsburgh, PA 15213. Tel.: 412-692-2117; Fax: 412-692-2260; E-mail: choiam{at}

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