PPAR gamma ligands, 15-deoxy-delta12,14-prostaglandin J2 and rosiglitazone regulate human cultured airway smooth muscle proliferation through different mechanisms.
The influence of two peroxisome proliferator-activated receptor gamma (PPARgamma) ligands, a thiazolidinedione, rosiglitazone (RG) and the prostaglandin D2 metabolite 15-deoxy-Delta(12,14)-prostaglandin J2 (15d-PGJ2) on the proliferation of human cultured airway smooth muscle (HASM) was examined. The increases in HASM cell number in response to basic fibroblast growth factor (bFGF, 300 pm) or thrombin (0.3 U ml-1) were significantly inhibited by either RG (1-10 microM) or 15d-PGJ2 (1-10 microM). The effects of RG, but not 15d-PGJ2, were reversed by the selective PPARgamma antagonist GW9662 (1 microM). Neither RG nor 15d-PGJ2 (10 microM) decreased cell viability, or induced apoptosis, suggesting that the regulation of cell number was due to inhibition of proliferation, rather than increased cell death. Flow-cytometric analysis of HASM cell cycle distribution 24 h after bFGF addition showed that RG prevented the progression of cells from G1 to S phase. In contrast, 15d-PGJ2 caused an increase in the proportion of cells in S phase, and a decrease in G2/M, compared to bFGF alone. Neither RG nor 15d-PGJ2 inhibited ERK phosphorylation measured 6 h post mitogen addition. The bFGF-mediated increase in cyclin D1 protein levels after 8 h was reduced in the presence of 15d-PGJ2, but not RG. Although both RG and 15d-PGJ2 can inhibit proliferation of HASM irrespective of the mitogen used, only the antiproliferative effects of RG appear to be PPARgamma-dependent. The different antimitogenic mechanisms of 15d-PGJ2 and synthetic ligands for PPARgamma may be exploited to optimise the potential for these compounds to inhibit airway remodelling in asthma. British Journal of Pharmacology (2004) 141, 517-525. doi:10.1038/sj.bjp.0705630
Ward
Jane E
JE
Department of Pharmacology, University of Melbourne, Melbourne, Victoria 3010, Australia. janeew@unimelb.edu.au
Gould
Haslinda
H
Harris
Trudi
T
Bonacci
John V
JV
Stewart
Alastair G
AG
D001980:Bronchi / Q000166:cytology / Q000187:drug effects*; D002452:Cell Count / Q000379:methods; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D006801:Humans; D008024:Ligands; D009130:Muscle, Smooth / Q000166:cytology / Q000187:drug effects*; D015230:Prostaglandin D2 / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology*; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000378:metabolism / Q000494:pharmacology*; D014157:Transcription Factors / Q000378:metabolism / Q000494:pharmacology*
C477819:15-deoxyprostaglandin J2; D008024:Ligands; D018160:Receptors, Cytoplasmic and Nuclear; D045162:Thiazolidinediones; D014157:Transcription Factors; D000077154:Rosiglitazone; D015230:Prostaglandin D2