Carbon monoxide modulates endotoxin-induced production of granulocyte macrophage colony-stimulating factor in macrophages
Carbon monoxide modulates endotoxin-induced production of granulocyte macrophage colony-stimulating factor in macrophages
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DOI：
10.1165/rcmb.4816
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发表时间：
2002-12-01
影响因子：
6.4
通讯作者：
Choi, AMK
中科院分区：
文献类型：
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作者：
Sarady, JK;Otterbein, SL;Choi, AMK
应激诱导基因血红素加氧酶-1（HO-1）提供对氧化应激的保护。虽然HO-1发挥其细胞保护作用的机制尚不清楚，但据推测，HO-1催化血红素后的催化副产物一氧化碳（CO）可能通过其抗炎特性介导细胞保护作用。粒细胞巨噬细胞集落刺激因子（GMCSF）是一种有效的细胞因子，在细菌内毒素（脂多糖[LPS]）刺激白细胞的增殖，成熟和效应功能，有助于对LPS的促炎反应。我们推测HO-1和/或CO可以调节GM-CSF的表达和产生。HO-1过表达，以及暴露于低浓度的CO，抑制LPS诱导的巨噬细胞GM-CSF的生产。此外，CO通过抑制转录因子NF-κ B的活化来抑制LPS诱导的GMCSF诱导。CO通过阻止调节亚基IkappaB-α的磷酸化和降解来抑制LPS诱导的NF-κ B活化，NF-κ B已被证明可调节GM-CSF转录。这些数据提出了一种有趣的可能性，即低浓度的CO可能在炎症性疾病状态中起重要作用，因此具有潜在的治疗意义。
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 (GMCSF) 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 GMCSF induction via inhibition in the activation of the transcription factor NF-kappaB. CO inhibited LPS-induced activation of NF-kappaB, which has been shown to regulate GM-CSF transcription, by preventing the phosphorylation and degradation of the regulatory subunit IkappaB-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.