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

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-B. CO inhibited LPS-induced activation of NF-B, which has been shown to regulate GM-CSF transcription, by preventing the phosphorylation and degradation of the regulatory subunit IB-. 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-B, NF-B • parts per million, ppm • sodium dodecyl sulfate, SDS

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