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American Journal of Respiratory Cell and Molecular Biology. Vol. 27, pp. 739-745, 2002
© 2002 American Thoracic Society
DOI: 10.1165/rcmb.4816

Carbon Monoxide Modulates Endotoxin-Induced Production of Granulocyte Macrophage Colony-Stimulating Factor in Macrophages

Judit K. Sarady, Sherrie L. Otterbein, Fang Liu, Leo E. Otterbein and Augustine M. K. Choi

Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania

Address correspondence to: Leo E. Otterbein, Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh School of Medicine, 3459 5th Avenue, MUH628, Pittsburgh, PA 15213. E-mail: otterbeinl{at}msx.upmc.edu

The stress-inducible gene heme oxygenase-1 (HO-1) provides protection against oxidative stress. Although the mechanisms by which HO-1 exerts its cytoprotection are not clearly understood, it has been speculated that carbon monoxide (CO), a catalytic byproduct following heme catabolism by HO-1, may mediate cellular cytoprotection via its anti-inflammatory properties. Granulocyte macrophage colony-stimulating factor (GM-CSF) is a potent cytokine generated in response to bacterial endotoxin (lipopolysaccharide [LPS]) to stimulate proliferation, maturation, and effector functions of leukocytes, contributing to the proinflammatory responses to LPS. We hypothesized that HO-1 and/or CO could regulate the expression and production of GM-CSF. HO-1 overexpression, as well as exposure to a low concentration of CO, inhibited LPS-induced GM-CSF production in macrophages. Furthermore, CO inhibited LPS-induced GM-CSF induction via inhibition in the activation of the transcription factor NF-{kappa}B. CO inhibited LPS-induced activation of NF-{kappa}B, which has been shown to regulate GM-CSF transcription, by preventing the phosphorylation and degradation of the regulatory subunit I{kappa}B-{alpha}. These data raise the intriguing possibility that CO at low concentrations may play an important role in inflammatory disease states and thus has potential therapeutic implications.

Abbreviations: bronchoalveolar lavage fluid, BALF • carbon monoxide, CO • enzyme-linked immunosorbent assay, ELISA • electrophoretic mobility shift assay, EMSA • granulocyte macrophage–colony-stimulating factor, GM-CSF • heme oxygenase-1, HO-1 • lipopolysaccharide, LPS • mitogen-activated protein, MAP • nuclear factor-{kappa}B, NF-{kappa}B • parts per million, ppm • sodium dodecyl sulfate, SDS




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