Signaling mechanisms of growth hormone-releasing hormone receptor in LPS-induced acute ocular inflammation.
Liang. Wei Cheng WC; Ren. Jia Lin JL; Yu. Qiu Xiao QX; Li. Jian J; Ng. Tsz Kin TK; Chu. Wai Kit WK; Qin. Yong Jie YJ; Chu. Kai On KO; Schally. Andrew V AV; Pang. Chi Pui CP; Chan. Sun On SO
Key Findings
- LPS triggers GHRH‑R up‑regulation and p65 phosphorylation in eye cells
- GHRH‑R directly interacts with JAK2, leading to STAT3 activation and higher IL‑6, IL‑17A, COX2, iNOS levels
- Antagonizing GHRH‑R with MIA‑602 or inhibiting JAK2 with Ruxolitinib reduces STAT3 phosphorylation and inflammatory markers
Practical Outcomes
- For biohackers, the work suggests that GHRH‑R activity can worsen acute eye inflammation, but the findings are limited to laboratory models and use specialized antagonists, not sermorelin. There’s no clear protocol for using sermorelin or related peptides to improve longevity or metabolic health based on this study.
Summary
The study shows that the receptor for growth‑hormone‑releasing hormone (GHRH‑R) helps drive eye inflammation by activating a JAK2‑STAT3 signaling chain, and that blocking this receptor or using a JAK inhibitor can calm the inflammation in animal and cell models.
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.
Study Information
pubmed
2020
2020-03-02T00:00:00.000Z
10.1073/pnas.1904532117
31
39