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Kazuhiro Kimura, Hongyan Zhou, Tomoko Orita, Masaaki Kobayashi, Teruo Nishida, Koh-Hei Sonoda; Suppression by an RAR-γ Agonist of Collagen Degradation Mediated by Corneal Fibroblasts. Invest. Ophthalmol. Vis. Sci. 2017;58(4):2250-2257. doi: 10.1167/iovs.15-18701.
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© 2017 Association for Research in Vision and Ophthalmology.
To examine the role of retinoic acid receptor (RAR) isoforms in interleukin-1β (IL-1β)–induced collagen degradation by corneal fibroblasts.
Primary rabbit corneal fibroblasts embedded in a three-dimensional collagen gel were incubated with or without all-trans retinoic acid (ATRA), the RAR-α agonist Am580, the RAR-β agonist AC55649, or the RAR-γ agonist R667. Collagen degradation was determined by measurement of hydroxyproline produced in acid hydrolysates of culture supernatants. Matrix metalloproteinase (MMP) expression was evaluated by immunoblot analysis and gelatin zymography. The phosphorylation of mitogen-activated protein kinases (MAPKs) and the endogenous nuclear factor (NF)–κB inhibitor IκB-α was examined by immunoblot analysis. Cell proliferation was measured with a bromodeoxyuridine incorporation assay, and cell viability was determined by measurement of the release of lactate dehydrogenase.
Interleukin-1β–induced collagen degradation by corneal fibroblasts was inhibited by ATRA, Am580, and R667 in a concentration-dependent manner but was unaffected by AC55649, with the inhibitory effects of ATRA and R667 being markedly greater than that of Am580. The IL-1β–induced production of MMP-1, MMP-2, MMP-3, and MMP-9 by corneal fibroblasts was also inhibited by R667 in a concentration-dependent manner. R667 inhibited the IL-1β–induced phosphorylation of IκB-α but not that of MAPKs. R667 had no effect on the proliferation or viability of corneal fibroblasts.
The RAR-γ agonist R667 suppressed MMP production and thereby inhibited collagen degradation by corneal fibroblasts exposed to the proinflammatory cytokine IL-1β. These effects of R667 may be mediated by the NF-κB signaling pathway.
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