title: Carbon monoxide inhibits T lymphocyte proliferation via caspase-dependent pathway.
abstract: T lymphocyte activation and proliferation is involved in many pathological processes. We have recently shown that carbon monoxide (CO), an enzymatic product of heme oxygenase-1 (HO-1), confers potent antiproliferative effects in airway and vascular smooth muscle cells. The purpose of this study was to determine whether CO can inhibit T lymphocyte proliferation and then to determine the mechanism by which CO can modulate T lymphocyte proliferation. In the presence of 250 parts per million CO, CD3-activated T lymphocyte proliferation was, remarkably, inhibited by 80% when compared with controls. We observed that the antiproliferative effect of CO in T lymphocytes was independent of the mitogen-activated protein kinase or cGMP signaling pathways, unlike what we demonstrated previously in smooth muscle cells. We demonstrate that CO inhibited caspase-3 and caspase-8 expression and activity, and caspase inhibition with benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone (Z-VAD-FMK pan-caspase inhibitor) blocked T lymphocyte proliferation. Furthermore, in caspase-8-deficient lymphocytes, the antiproliferative effect of CO was markedly attenuated, further supporting the involvement of caspase-8 in the antiproliferative effects of CO. CO also increased the protein level of p21(Cip1), and CO-mediated inhibition of caspase activity is partially regulated by p21(Cip1). Taken together, these data suggest that CO confers potent antiproliferative effects in CD3-activated T lymphocytes and that these antiproliferative effects in T lymphocytes are mediated by p21(Cip1)-dependent caspase activity, in particular caspase-8, independent of cGMP and mitogen-activated protein kinase signaling pathways.
authors.affiliation: Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh School of Medicine, 3459 5th Avenue, Pittsburgh, PA 15213, USA.
authors.forename: Ruiping
authors.initials: R
authors.lastname: Song
authors.forename: Raja S
authors.initials: RS
authors.lastname: Mahidhara
authors.forename: Zhihong
authors.initials: Z
authors.lastname: Zhou
authors.forename: Rosemary A
authors.initials: RA
authors.lastname: Hoffman
authors.forename: Dai-Wu
authors.initials: DW
authors.lastname: Seol
authors.forename: Richard A
authors.initials: RA
authors.lastname: Flavell
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Billiar
authors.forename: Leo E
authors.initials: LE
authors.lastname: Otterbein
authors.forename: Augustine M K
authors.initials: AM
authors.lastname: Choi
mesh_terms: D000818:Animals; D002248:Carbon Monoxide / Q000633:toxicity*; D053181:Caspase 8; D061945:Caspase Inhibitors; D020169:Caspases / Q000502:physiology*; D002478:Cells, Cultured; D006152:Cyclic GMP / Q000096:biosynthesis; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000096:biosynthesis; D004789:Enzyme Activation / Q000187:drug effects / Q000276:immunology; D004791:Enzyme Inhibitors / Q000633:toxicity; D006131:Growth Inhibitors / Q000633:toxicity*; D006162:Guanylate Cyclase / Q000378:metabolism / Q000502:physiology; D006801:Humans; D007166:Immunosuppressive Agents / Q000633:toxicity*; D048031:JNK Mitogen-Activated Protein Kinases; D019169:Jurkat Cells; D008213:Lymphocyte Activation / Q000187:drug effects; D048670:MAP Kinase Kinase 4; D048748:MAP Kinase Kinase Kinase 3; D020930:MAP Kinase Kinase Kinases / Q000502:physiology; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020929:Mitogen-Activated Protein Kinase Kinases / Q000502:physiology; D013601:T-Lymphocytes / Q000187:drug effects* / Q000201:enzymology* / Q000276:immunology / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects / Q000276:immunology
chemical_list: C493956:CDKN1A protein, human; D061945:Caspase Inhibitors; C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004791:Enzyme Inhibitors; D006131:Growth Inhibitors; D007166:Immunosuppressive Agents; D002248:Carbon Monoxide; D048031:JNK Mitogen-Activated Protein Kinases; D048748:MAP Kinase Kinase Kinase 3; D020930:MAP Kinase Kinase Kinases; C482625:MAP3K3 protein, human; C482626:Map3k3 protein, mouse; D048670:MAP Kinase Kinase 4; D020929:Mitogen-Activated Protein Kinase Kinases; C505530:CASP8 protein, human; C505526:Casp8 protein, mouse; D053181:Caspase 8; D020169:Caspases; D006162:Guanylate Cyclase; D006152:Cyclic GMP