ITF2357 inhibits corneal fibrosis and inflammation via JAK/STAT3 signaling pathway
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1
SINGAPORE EYE RESEARCH INSTITUTE, Singapore
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2
DUKE-NUS Graduate Medical School, Singapore
Purpose: In this study, we investigated the mechanism of action of a histone deacetylase inhibitor, ITF2357 on fibrosis and inflammation in a corneal wound healing model.
Methods: In vivo experiments were conducted with 20 rabbits that 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). In vitro experiments were performed with cultured primary human corneal fibroblasts (pHCFs) to study the ITF2357-induced activation of IL-10 and JAK/STAT signaling pathway using specific signaling inhibitors by immunocytochemistry, western blot and ELISA.
Results: ITF2357 is non-toxic and effective in nM concentrations to significantly reduce corneal haze and extracellular matrix formation on IVCM and immunohistochemitry. 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.
Conclusions:ITF2357 upregultes IL-10 levels via activation of JAK/STAT signaling pathway to inhibit fibrotic and inflammatory activity in corneal disease model.
Acknowledgements
We will like to acknowledge grants from SingHealth Foundation [R756/40/2010 SHF; R729/13/2010 SHF] to SSC and National Medical Research Council-Funded NIG award [R751/35/2010 NMRC] to SSC. ITF2357 was a kind donation by Prof. Paolo Mascagni from Italfarmaco S.p.A., ITALY.
Keywords:
Inflammation,
IL-10,
HDACi,
phototherpeutic keratectomy,
Fibroblasts
Conference:
15th International Congress of Immunology (ICI), Milan, Italy, 22 Aug - 27 Aug, 2013.
Presentation Type:
Abstract
Topic:
Translational immunology and immune intervention
Citation:
CHAURASIA
SS,
Tan
A,
Lim
R,
Liu
Y and
Mehta
JS
(2013). ITF2357 inhibits corneal fibrosis and inflammation via JAK/STAT3 signaling pathway.
Front. Immunol.
Conference Abstract:
15th International Congress of Immunology (ICI).
doi: 10.3389/conf.fimmu.2013.02.00812
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Received:
20 Jun 2013;
Published Online:
22 Aug 2013.
*
Correspondence:
Dr. SHYAM S CHAURASIA, SINGAPORE EYE RESEARCH INSTITUTE, SINGAPORE, Singapore, schaurasia@mcw.edu