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

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.

Protective effects of growth hormone-releasing hormone analogs in DSS-induced colitis in mice

“…The involvement of the somatotropic axis in inflammatory states is well known 32 , 33 . Various agonist and antagonist analogs of GHRH have shown marked antinflammatory effects 16 , 19 , 27 , 34 – 36 . In particular, MIA-690 inhibited inflammation by reducing the production of inflammatory markers in carrageenan-induced chronic prostatitis 35 .…”

Coniferyl Aldehyde Inhibits the Inflammatory Effects of Leptomeningeal Cells by Suppressing the JAK2 Signaling

“…Another research showed that LPS stimulated the expression of NF- κ B subunit p65 in human ciliary epithelial cells, resulting in the activation of receptor for growth-hormone-releasing hormone (GHRH-R). The downstream JAK2 is phosphorylated and augments the production of proinflammatory factors [ 43 ]. Therefore, we speculate that JAK2 is likely to be a downstream molecular target of CatB/NF- κ B in the macrophage-mediated inflammatory reaction induced by P. gingivalis .…”

Protective Effects of Fucoxanthin Dampen Pathogen-Associated Molecular Pattern (PAMP) Lipopolysaccharide-Induced Inflammatory Action and Elevated Intraocular Pressure by Activating Nrf2 Signaling and Generating Reactive Oxygen Species

“…Uveitis is a general term describing a group of intraocular inflammatory diseases that often affect the uvea [8]. Injection of LPS can generate PAMP-induced uveitis, which is widely used as an animal model to examine the pathological mechanisms of uveitis and ophthalmic inflammation in animals [9][10][11]. In a state of inflammation, the uveal tract, including the iris, shows the accumulation of inflammatory cells.…”