Rosiglitazone activation of PPARgamma suppresses fractalkine signaling.
The nuclear receptor peroxisome proliferator-activated receptor gamma (PPARgamma) is a key transcriptional regulator of both lipid metabolism and inflammation. The importance of PPARgamma is accentuated by the widespread use of synthetic PPARgamma agonists, thiazolidinediones (such as rosiglitazone), as drugs for insulin resistance and type II diabetes. Fractalkine (FKN) and FKN 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 PPARgamma activation and FKN signaling. On one hand, the activation of PPARgamma 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, the activation of PPARgamma by rosiglitazone in endothelial cells also impedes the nuclear export of FKN. Together, these data suggest that PPARgamma activation represses FKN signaling. These findings indicate a previously unrecognized mechanism that may contribute to the anti-inflammatory effect of PPARgamma.
Department of Pharmacology, University of Texas Southwestern Medical Center, 6001 Forest Park Road, Room ND8.502B, Dallas, Texas 75390-9041, USA. yihong.wan@utsouthwestern.edu
Yihong
Y
Wan
Ronald M
RM
Evans
D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000818:Animals; D002460:Cell Line; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D054428:Chemokine CX3CL1 / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation / Q000187:drug effects; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D047495:PPAR gamma / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D021381:Protein Transport / Q000187:drug effects; D000077154:Rosiglitazone; D015398:Signal Transduction / Q000187:drug effects*; D045162:Thiazolidinediones / Q000494:pharmacology*
D054428:Chemokine CX3CL1; D047495:PPAR gamma; D045162:Thiazolidinediones; D000077154:Rosiglitazone