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

Proc Natl Acad Sci U S A. 2020 Mar 17;117(11):6067-6074. doi: 10.1073/pnas.1904532117. Epub 2020 Mar 2.


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.

Keywords: GHRH-R; JAK2/STAT3 pathway; LPS; inflammation; uveitis.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Cell Line
  • Ciliary Body / cytology
  • Disease Models, Animal
  • Epithelial Cells / drug effects
  • Epithelial Cells / immunology
  • Epithelial Cells / pathology*
  • Humans
  • Janus Kinase 2 / metabolism
  • Lipopolysaccharides / immunology
  • Male
  • Nitriles
  • Pyrazoles / pharmacology
  • Pyrazoles / therapeutic use
  • Pyrimidines
  • Rats
  • Receptors, Neuropeptide / antagonists & inhibitors
  • Receptors, Neuropeptide / immunology
  • Receptors, Neuropeptide / metabolism*
  • Receptors, Pituitary Hormone-Regulating Hormone / antagonists & inhibitors
  • Receptors, Pituitary Hormone-Regulating Hormone / immunology
  • Receptors, Pituitary Hormone-Regulating Hormone / metabolism*
  • STAT3 Transcription Factor / metabolism
  • Sermorelin / analogs & derivatives
  • Sermorelin / pharmacology
  • Sermorelin / therapeutic use
  • Signal Transduction / drug effects
  • Signal Transduction / immunology*
  • Uveitis / drug therapy
  • Uveitis / immunology
  • Uveitis / pathology*


  • GHRH(1-29)NH2, (PhAc-Ada)(0)-Tyr(1), Arg(2), Fpa(5,6), Ala(8), Har(9), Tyr(Me)(10), His(11), Orn(12,) Abu(15), His(20), Orn(21), Nle(27), Arg(28), Har(29)-
  • GHRHR protein, human
  • Lipopolysaccharides
  • Nitriles
  • Pyrazoles
  • Pyrimidines
  • Receptors, Neuropeptide
  • Receptors, Pituitary Hormone-Regulating Hormone
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • Stat3 protein, rat
  • ruxolitinib
  • Sermorelin
  • JAK2 protein, human
  • Jak2 protein, rat
  • Janus Kinase 2