title: 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.
authors.affiliation: Department of Microbiology and Immunology, School of Medicine, Wonkwang University, Iksan, Chonbuk, Republic of Korea.
authors.forename: Hyun-Ock
authors.initials: HO
authors.lastname: Pae
authors.forename: Gi-Su
authors.initials: GS
authors.lastname: Oh
authors.forename: Byung-Min
authors.initials: BM
authors.lastname: Choi
authors.forename: Soo-Cheon
authors.initials: SC
authors.lastname: Chae
authors.forename: Young-Myeong
authors.initials: YM
authors.lastname: Kim
authors.forename: Khee-Rhin
authors.initials: KR
authors.lastname: Chung
authors.forename: Hun-Taeg
authors.initials: HT
authors.lastname: Chung
mesh_terms: D015496:CD4-Positive T-Lymphocytes / Q000201:enzymology / Q000276:immunology; D002248:Carbon Monoxide / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology*; D002453:Cell Cycle / Q000276:immunology; D006152:Cyclic GMP / Q000502:physiology; D015536:Down-Regulation / Q000276:immunology; D004791:Enzyme Inhibitors / Q000378:metabolism / Q000494:pharmacology; D006131:Growth Inhibitors / Q000096:biosynthesis* / Q000502:physiology; D006162:Guanylate Cyclase / Q000502:physiology; D006419:Heme Oxygenase (Decyclizing) / Q000096:biosynthesis / Q000502:physiology*; D051547:Heme Oxygenase-1; D006801:Humans; D007166:Immunosuppressive Agents / Q000378:metabolism* / Q000494:pharmacology; D016753:Interleukin-10 / Q000502:physiology; D007376:Interleukin-2 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis* / Q000378:metabolism; D019169:Jurkat Cells; D008213:Lymphocyte Activation / Q000276:immunology; D020935:MAP Kinase Signaling System / Q000276:immunology; D008565:Membrane Proteins; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000201:enzymology* / Q000276:immunology* / Q000378:metabolism; D014162:Transfection
chemical_list: D004791:Enzyme Inhibitors; D006131:Growth Inhibitors; D007166:Immunosuppressive Agents; D007376:Interleukin-2; D008565:Membrane Proteins; D016753:Interleukin-10; D002248:Carbon Monoxide; C496541:HMOX1 protein, human; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D006162:Guanylate Cyclase; D006152:Cyclic GMP