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Shyam Chaurasia, Yu-Chi Liu, Alison Tan, Rayne Lim, Jodhbir Mehta; ITF2357 regulates IL-10 via JAK/STAT signaling pathway to attenuate inflammation and fibrosis. Invest. Ophthalmol. Vis. Sci. 2013;54(15):117.
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To study the mechanism of action of a histone deacetylase inhibitor, ITF2357 on fibrosis and inflammation in vitro and in vivo in a rabbit PRK model of corneal wound healing.
Twenty rabbits underwent -9.0D photorefractive keratectomy (PRK) surgery in one eye and were divided into 3 groups based on post-op treatment with a single dose of saline (3 days), ITF2357 (0.02% for 3 days) or MMC (0.02% for 60 sec post-surgery). Post-op clinical examination was made for 4 weeks using slit lamp microscopy and in vivo confocal microscopy (IVCM). Cultured primary human corneal fibroblasts (pHCFs) were used to study the ITF2357-induced activation of IL-10 and JAK/STAT signaling pathway using specific signaling inhibitors by immunocytochemistry, western blot and ELISA.
ITF2357 significantly reduced corneal haze and extracellular matrix formation on IVCM. IL-10 expression was up-regulated in the ITF2357 treated PRK corneas compared to the MMC treated. Cultured pHCFs with ITF2357 produced elevated levels of IL-10 in a time-dependent manner. This in turn, resulted in the activation of pSTAT3 and downstream signaling with overexpression of SOCS3 expression. Inhibition of recruitment of STAT3 to the receptor complex with a specific inhibitor blocked the phosphorylation of STAT3, preventing its nuclear entry and hence decreased IL-10 production.
ITF2357 activates IL-10 levels via activation of JAK/STAT signaling pathway to exhibits its anti-fibrotic and anti-inflammatory activity in cornea wound healing.
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