WY-14 643, a selective PPAR{alpha} agonist, induces proinflammatory and proangiogenic responses in human ocular cells.
Peroxisome proliferator-activated receptor α (PPARα) agonism in ocular inflammation has not been thoroughly investigated. The objective of this investigation was to determine the effect of WY-14 643, a selective PPARα agonist, on inflammatory cytokine release in human ocular cells. Stimulation of primary human corneal epithelial cells, keratocytes, and retinal endothelial cells with 1 to 10 ng/mL interleukin 1β (IL-1β) resulted in a significant increase in numerous inflammatory cytokines, including IL-6, IL-8, and tumor necrosis factor α (TNF-α); and dexamethasone was able to significantly inhibit these effects. However, WY-14 643 did not effectively block IL-1β-induced cytokine release in ocular cells; rather, significant increases in IL-1β-induced inflammatory cytokines were observed in these cells but not in aortic smooth muscle cells. WY-14 643 also significantly upregulated vascular endothelial growth factor (VEGF) expression in corneal epithelial cells and keratocytes. These studies demonstrate for the first time that PPARα agonism may be proinflammatory and proangiogenic in a variety of ocular cells and suggest that therapeutic applications of such agents in ophthalmology may be limited.
Zhang
Jin-Zhong
JZ
Pharmaceutical R&D, Bausch & Lomb, Inc, 1400 North Goodman Street, Rochester, NY 14603, USA. jinzhong_zhang@bausch.com
Ward
Keith W
KW
D043925:Angiogenesis Inducing Agents / Q000633:toxicity; D002478:Cells, Cultured; D003115:Colony-Stimulating Factors / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D019573:Epithelium, Corneal / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005123:Eye / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D006801:Humans; D007249:Inflammation / Q000139:chemically induced / Q000378:metabolism; D018836:Inflammation Mediators / Q000378:metabolism*; D053583:Interleukin-1beta / Q000378:metabolism / Q000494:pharmacology; D007378:Interleukins / Q000378:metabolism; D009928:Organ Specificity; D047493:PPAR alpha / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D020025:Peroxisome Proliferators / Q000633:toxicity*; D011743:Pyrimidines / Q000633:toxicity*; D012333:RNA, Messenger / Q000378:metabolism; D012160:Retina / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D042442:Vascular Endothelial Growth Factors / Q000378:metabolism
D043925:Angiogenesis Inducing Agents; D003115:Colony-Stimulating Factors; D016207:Cytokines; D018836:Inflammation Mediators; D053583:Interleukin-1beta; D007378:Interleukins; D047493:PPAR alpha; D020025:Peroxisome Proliferators; D011743:Pyrimidines; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D042442:Vascular Endothelial Growth Factors; C006253:pirinixic acid