Carbon monoxide produced by heme oxygenase-1 suppresses T cell proliferation via inhibition of IL-2 production
Carbon monoxide produced by heme oxygenase-1 suppresses T cell proliferation via inhibition of IL-2 production
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DOI：
10.4049/jimmunol.172.8.4744
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发表时间：
2004-04-15
影响因子：
4.4
通讯作者：
Chung, HT
中科院分区：
文献类型：
--
作者：
Pae, HO;Oh, GS;Chung, HT
血红素加氧酶-1（HO-1）将血红素分解代谢为CO、胆绿素和游离铁，并通过其抗炎、抗凋亡和抗增殖作用而作为保护酶。以前，我们已经证明了人CD 4（+）T细胞表达HO-1，而HO-1过表达的Jurkat T细胞倾向于显示较低的增殖反应。本研究旨在阐明HO-1对CD 4（+）T细胞抗增殖作用的机制。在这三种HO-1副产物中，只有CO显示出对T细胞增殖的抑制作用，以响应抗-CD 3加抗-CD 28 Ab，模拟HO-1的抗增殖作用。CO阻断了T细胞进入细胞周期的能力，这是不依赖于鸟苷酸环化酶/cGMP途径的。CO还抑制IL-2的分泌，这种抑制IL-2分泌的作用是通过CO的抗增殖作用介导的，CO选择性地抑制细胞外信号调节激酶途径，这可以解释CO抑制T细胞增殖和IL-2分泌的作用。基于这些发现，我们认为HO-1/CO抑制T细胞增殖和IL-2的分泌，可能通过其抑制细胞外信号调节激酶的激活。
Heme oxygenase-1 (HO-1) catabolizes heme into CO, biliverdin, and free iron and serves as a protective enzyme by virtue of its anti-inflammatory, antiapoptotic, and antiproliferative actions. Previously, we have demonstrated that human CD4(+) T cells express HO-1 and that HO-1-overexpressing Jurkat T cells tend to display lower proliferative response. The aim of this study is to elucidate the mechanism(s) by which HO-1 can mediate its antiproliferative effect on CD4(+) T cells. Among the three HO-1 byproducts, only CO showed suppressive effect on T cell proliferation in response to anti-CD3 plus anti-CD28 Abs, mimicking the antiproliferative action of HO-1. CO blocked the cell cycle entry of T cells, which was independent of the guanylate cyclase/cGMP pathway. CO also suppressed the secretion of IL-2, and this suppressive effect of CO on IL-2 secretion mediated the antiproliferative action of CO. CO selectively inhibited the extracellular signal-regulated kinase pathway, which could explain the suppressive effects of CO on T cell proliferation and IL-2 secretion. Based on these findings, we suggest that HO-1/CO suppresses T cell proliferation and IL-2 secretion, possibly via its inhibition of extracellular signal-regulated kinase activation.