Carbon Monoxide Produced by Heme Oxygenase-1 Suppresses T Cell Proliferation via Inhibition of IL-2 Production

Abstract

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.

Micro‐RNA‐155‐mediated control of heme oxygenase 1 (HO‐1) is required for restoring adaptively tolerant CD4+ T‐cell function in rodents

“…Little is known about how HO-1 expression in T cells affects their function. Pae et al have documented that CO produced by HO-1 activity in human T cells inhibited IL-2 secretion and proliferation [28]. HO-1 expression in effector T cells was also shown to induce Fas-mediated apoptosis [29].…”

“…It is also known that miR-155-deficient splenic T cells exhibit a specific defect in IL-2 production following antigenic stimulation [12]. Interestingly, HO-1 expression in T cells has previously been reported to inhibit IL-2 production directly or by inducing apoptosis of IL-2-producing cells [28,29]. We then set up experiments aimed at analyzing how HO-1 inhibition could affect IL-2 secretion by miR-155 −/− T cells.…”

CD4+CD25+FoxP3+ T-cell infiltration and heme oxygenase-1 expression correlate with tumor grade in human gliomas

“…The exact role of HO-1 expression is not fully understood in T-cells. However, growing evidence has shown that HO-1 and its byproduct, CO, suppress T-cell proliferation [34,35]. The over-expression of HO-1 results in the inhibition of several immune effector functions and thus provides an explanation for stressinduced immunosuppression [36].…”

HO‐1 promoter polymorphism associated with rheumatoid arthritis

“…HO-1 induction leads to the suppression of T cell proliferation and IL-2 secretion and to the inhibition of class II major histocompatibility complex molecule expression in antigen-presenting cells (23,24). In addition, HO-1 expression occurs in Treg cells in a manner analogous to their specific transcription factor FoxP3 (3).…”