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Seung Ah Chung, Bo Kyung Jeon, Youn-Hee Choi, Keum Ok Back, Jong Bok Lee, Koung Hoon Kook; Pirfenidone Attenuates the IL-1β–Induced Hyaluronic Acid Increase in Orbital Fibroblasts From Patients With Thyroid-Associated Ophthalmopathy. Invest. Ophthalmol. Vis. Sci. 2014;55(4):2276-2283. doi: https://doi.org/10.1167/iovs.13-13759.
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This study aimed to investigate the effect of pirfenidone on the IL-1β–induced hyaluronic acid (HA) increase in orbital fibroblasts from patients with thyroid-associated ophthalmopathy (TAO).
Primary cultured orbital fibroblasts were obtained from patients with TAO, and the excreted levels of HA from IL-1β–treated cells with or without pirfenidone were measured. The effect of pirfenidone on IL-1β–induced hyaluronic acid synthase (HAS) expression was evaluated. The relevance of the mitogen-activated protein kinase (MAPK)–mediated signaling pathway in IL-1β–induced HAS expression was assessed using specific inhibitors to p38, extracellular signal-regulated kinase (ERK), or c-Jun N-terminal kinase (JNK). The phosphorylation level of each MAPK in IL-1β–treated cells with or without pirfenidone and the level of AP-1 DNA binding were measured. The inhibitory potency of pirfenidone on HA production was evaluated using dexamethasone as a reference agent.
Pirfenidone strongly attenuated the IL-1β–induced HA release in a dose-dependent manner. The IL-1β–induced HAS expression was decreased significantly following cotreatment with pirfenidone at the mRNA and protein levels. The production of mRNAs was halted by cotreatment with inhibitors of ERK and p38, but not by inhibitors of JNK. The IL-1β–induced ERK and p38 phosphorylation, and AP-1 DNA binding were attenuated in the presence of pirfenidone. Pirfenidone showed greater potency than dexamethasone in inhibiting increases in IL-1β–induced HA.
Pirfenidone attenuates the IL-1β–induced HA production in orbital fibroblasts from patients with TAO, at least in part, through suppression of the MAPK-mediated HAS expression. These results support the potential use of pirfenidone for treatment of patients with TAO.
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