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-2d) islets in which PPARγ activity was induced by its agonists, 15-deoxy-Δ12-14-prostaglandin J2 (15d-PGJ2) or troglitazone were transplanted into C57BL/6 (H-2b) 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.
Document Type: Research Article
Affiliations: Department of Surgery, Medical University of South Carolina, Charleston, SC, USA
Publication date: 2012-10-01
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