Activation of Peroxisome Proliferator-Activated Receptor γ Prolongs Islet Allograft Survival

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 gamma (PPAR gamma), a transcriptional regulator, in isolated islets. In this study, we evaluated whether PPAR gamma contributes to the survival and function of transplanted islets and whether PPAR gamma mediates the protective effect of CO in a major mismatch islet allogeneic transplantation model. BALB/c (H-2(d)) islets in which PPAR gamma activity was induced by its agonists, 15-deoxy-Delta(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 PPAR gamma activation in islets led to a high percentage of BALB/c islets survived long-term in C57BL/6 recipients. Activation of PPAR gamma in the donor suppresses expressions of proinflammatory cytokines including tumor necrosis factor-alpha (TNF-alpha) and inducible nitric oxide synthase (iNOS) in transplanted islets. Blocking PPAR gamma activity by its antagonist, GW9662, abrogated the donor effect of CO in vivo and in vitro. Our data demonstrate that PPAR gamma 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 PPAR gamma.