title: Activation of peroxisome proliferator-activated receptor γ prolongs islet allograft survival.
abstract: Exposing donor mice to carbon monoxide (CO) protects transplanted islet allografts from immune rejection after transplantation (referred as the "donor" effect). In an attempt to understand the mechanisms of the donor effect of CO, we found that donor treatment with CO upregulates  expression of peroxisome proliferator-activated receptor γ (PPARγ), a transcriptional regulator, in isolated islets. In this study, we evaluated whether PPARγ contributes to the survival and function of transplanted islets and whether PPARγ mediates the protective effect  of CO in a major mismatch islet allogeneic transplantation model. BALB/c (H-2(d)) islets in which PPARγ activity was induced by its agonists, 15-deoxy-Δ(12-14)-prostaglandin J(2) (15d-PGJ(2)) or troglitazone were transplanted into C57BL/6 (H-2(b))  recipients that had been rendered diabetic by streptozotocin (STZ). Blood glucose levels of recipients were monitored to determine the function of transplanted islets. Our data indicated that PPARγ activation in islets led to a high percentage of BALB/c islets survived long-term in C57BL/6  recipients. Activation of PPARγ in the donor suppresses expressions of proinflammatory cytokines including tumor necrosis factor-α (TNF-α) and inducible nitric oxide synthase (iNOS) in transplanted islets. Blocking PPARγ activity by its antagonist, GW9662, abrogated the donor effect  of CO in vivo and in vitro. Our data demonstrate that PPARγ plays a critical role in the survival and function of transplanted islets after transplantation in the recipient. The protective effects of CO are at least in part mediated by PPARγ.
authors.affiliation: Department of Surgery, Medical University of South Carolina, Charleston, SC 29425, USA. wangho@musc.edu
authors.forename: Hongjun
authors.initials: H
authors.lastname: Wang
authors.forename: Hongju
authors.initials: H
authors.lastname: Wu
authors.forename: Fredy
authors.initials: F
authors.lastname: Rocuts
authors.forename: Zhuoying
authors.initials: Z
authors.lastname: Gu
authors.forename: Fritz H
authors.initials: FH
authors.lastname: Bach
authors.forename: Leo E
authors.initials: LE
authors.lastname: Otterbein
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000276:immunology / Q000502:physiology; D002248:Carbon Monoxide / Q000494:pharmacology; D006085:Graft Survival / Q000187:drug effects / Q000502:physiology*; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism; D016381:Islets of Langerhans Transplantation / Q000379:methods*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D047495:PPAR gamma / Q000819:agonists / Q000378:metabolism*; D016019:Survival Analysis; D014184:Transplantation, Homologous; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D015854:Up-Regulation
chemical_list: D047495:PPAR gamma; D014409:Tumor Necrosis Factor-alpha; D002248:Carbon Monoxide; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse