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This Article Accepted manuscript (PDF) All Versions of this Article: JME-09-0090v1 44/2/135    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Wan, Y. Articles by Evans, R. M PubMed PubMed Citation Articles by Wan, Y. Articles by Evans, R. M

Y Wan, Pharmacology, University of Texas Southwestern Medical Center, Dallas, 75390-9041, United States
R Evans, Gene Expression Laboratory, Salk Institute, La Jolla, United States

Correspondence: Yihong Wan, Email: yihong.wan{at}utsouthwestern.edu

Abstract

The nuclear receptor PPAR (Peroxisome proliferator-activated receptor ) is a key transcriptional regulator of both lipid metabolism and inflammation. The importance of PPAR is accentuated by the widespread use of synthetic PPAR agonists, thiazolidinediones (TZDs, such as rosiglitazone), as drugs for insulin resistance and type II diabetes. Fractalkine (FKN) and fractalkine receptor (FR) play an important role in the immune responses by regulating leukocyte migration and adhesion to inflamed peripheral tissues. In this study, we have identified a novel link between PPAR activation and fractalkine signaling. On one hand, activation of PPAR by rosiglitazone in macrophages not only represses the transcription of the FR gene, but also prevents the plasma membrane translocation of the FR protein. On the other hand, activation of PPAR by rosiglitazone in endothelial cells also impedes the nuclear export of FKN. Together, these data suggest that PPAR activation represses fractalkine signaling. These findings provide a previously unrecognized mechanism that may contribute to the anti-inflammatory effect of PPAR.