Signaling mechanisms of growth hormone-releasing hormone receptor in LPS-induced acute ocular inflammation

Wei Cheng Liang, Jia Lin Ren, Qiu Xiao Yu, Jian Li, Tsz Kin Ng, Wai Kit Chu, Yong Jie Qin, Kai On Chu, Andrew V. Schally, Chi Pui Pang, Sun On Chan

Research output: Contribution to journalArticle

2 Scopus citations

Abstract

Ocular inflammation is a major cause of visual impairment attributed to dysregulation of the immune system. Previously, we have shown that the receptor for growth-hormone–releasing hormone (GHRH-R) affects multiple inflammatory processes. To clarify the pathological roles of GHRH-R in acute ocular inflammation, we investigated the inflammatory cascades mediated by this receptor. In human ciliary epithelial cells, the NF-κB subunit p65 was phosphorylated in response to stimulation with lipopolysaccharide (LPS), resulting in transcriptional up-regulation of GHRH-R. Bioinformatics analysis and coimmunoprecipitation showed that GHRH-R had a direct interaction with JAK2. JAK2, but not JAK1, JAK3, and TYK2, was elevated in ciliary body and iris after treatment with LPS in a rat model of endotoxin-induced uveitis. This elevation augmented the phosphorylation of STAT3 and production of proinflammatory factors, including IL-6, IL-17A, COX2, and iNOS. In explants of iris and ciliary body, the GHRH-R antagonist, MIA-602, suppressed phosphorylation of STAT3 and attenuated expression of downstream proinflammatory factors after LPS treatment. A similar suppression of STAT3 phosphorylation was observed in human ciliary epithelial cells. In vivo studies showed that blocking of the GHRH-R/JAK2/STAT3 axis with the JAK inhibitor Ruxolitinib alleviated partially the LPS-induced acute ocular inflammation by reducing inflammatory cells and protein leakage in the aqueous humor and by repressing expression of STAT3 target genes in rat ciliary body and iris and in human ciliary epithelial cells. Our findings indicate a functional role of the GHRH-R/JAK2/STAT3–signaling axis in acute anterior uveitis and suggest a therapeutic strategy based on treatment with antagonists targeting this signaling pathway.

Original languageEnglish (US)
Pages (from-to)6067-6074
Number of pages8
JournalProceedings of the National Academy of Sciences of the United States of America
Volume117
Issue number11
DOIs
StatePublished - Mar 17 2020

Keywords

  • GHRH-R
  • Inflammation
  • JAK2/STAT3 pathway
  • LPS
  • Uveitis

ASJC Scopus subject areas

  • General

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