Growth hormone-releasing hormone receptor mediates cytokine production in ciliary and iris epithelial cells during LPS-induced ocular inflammation

Ren, Jia Lin; Yu, Qiu Xiao; Ma, Ding; Liang, Wei; Leung, Pui Ying; Ng, Tsz Kin; Chu, Wai Kit; Pang, Chi Pui; Chan, Sun On

doi:10.1016/j.exer.2019.02.021

Cited by 19 publications

(11 citation statements)

References 21 publications

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“…Our earlier study has shown that GHRH-R is elevated specifically in the epithelium of ciliary body and iris after a LPS insult, which is associated with production of proinflammatory factors that causes influxes of protein and inflammatory cells from the blood vessels into the aqueous humor (10). These inflammatory reactions are likely caused by an activation of LPS receptor TLR4, which has been shown to express on the ciliary and iris epithelial cells, and the antigen-presenting cells in the stroma (19). Activation of TLR4 in resident macrophages and other antigen-presenting cells in the tissues and the systemic circulation triggers phosphorylation of NF-κB, which is translocated into the nucleus and switches on gene expression of proinflammatory factors (8,20,21).…”

Section: Discussionmentioning

confidence: 97%

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

Liang

Ren

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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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.

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Section: Discussionmentioning

confidence: 97%

“…They were housed in a 12:12-h light:dark cycle room and were allowed to freely access food and water. EIU was induced by a footpad injection of LPS at the dose of 1 mg/kg following our previous investigations (10,19). The JAK2 inhibitor Ruxolitinib was suspended in 25 μL DMSO and then resuspended in 475 μL distilled water.…”

Section: Methodsmentioning

confidence: 99%

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

Liang

Ren

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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“…MIA 602 suppresses the elevated expression of IL-1β and IL-6, and reduces the release of IL-6. 22 It has been a b c Figure 5. Effects of GHRH agonist MR 409 in the expression levels of pJAK2, pSTAT3, pERK1/2 in BPAEC.…”

Section: Discussionmentioning

confidence: 99%

GHRH antagonists support lung endothelial barrier function

et al. 2019

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Growth Hormone-Releasing Hormone (GHRH) regulates the release of growth hormone from the anterior pituitary gland. GHRH also acts as a growth and inflammatory factor in a variety of experimental models in oncology. In the current study, we used bovine pulmonary arterial cells in order to investigate the effects of GHRH and its antagonistic and agonistic analogs in key intracellular pathways that regulate endothelial permeability. GHRH antagonists suppressed the activation of MLC2, ERK1/2, JAK2/STAT3 pathway and increased the intracellular P53 and pAMPK levels. In contrast, both GHRH and GHRH agonist MR409 exerted the opposite effects. Furthermore, GHRH antagonists supported the integrity of endothelial barrier, while GHRH and GHRH agonists had the contrary effects, as reflected in measurements of transendothelial resistance. Our observations support the evidence for the antiinflammatory role of GHRH antagonists in the vasculature. Moreover, our results suggest that GHRH antagonists should be considered as promising therapeutic agents for treating severe respiratory abnormalities, such as the lethal Acute Respiratory Distress Syndrome (ARDS).

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“…GHRH-R antagonists decrease lipid peroxidation, protein carbonyls, and nitrotyrosine in prostate cancer cells [32], indicating antioxidant effects that would augment their other anti-inflammatory effects [33]. Both GH and IGF-1 stimulate neutrophil superoxide (O 2 − ) production [9].…”

Section: Discussionmentioning

confidence: 99%

Growth Hormone-Releasing Hormone Receptor Antagonist Modulates Lung Inflammation and Fibrosis due to Bleomycin

Zhang

Cai

Lazerson

et al. 2019

Lung

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PurposeGrowth hormone-releasing hormone (GHRH) is a 44-amino acid peptide that regulates growth hormone (GH) secretion. We hypothesized that a GHRH receptor (GHRH-R) antagonist, MIA-602, would inhibit bleomycin-induced lung inflammation and/or fibrosis in C57Bl/6J mice.MethodsWe tested whether MIA-602 (5 μg or vehicle given subcutaneously [SC] on days 1–21) would decrease lung inflammation (at day 14) and/or fibrosis (at day 28) in mice treated with intraperitoneal (IP) bleomycin (0.8 units on days 1, 3, 7, 10, 14, and 21). Bleomycin resulted in inflammation and fibrosis around airways and vessels evident histologically at days 14 and 28.ResultsInflammation (histopathologic scores assessed blindly) was visibly less evident in mice treated with MIA-602 for 14 days. After 28 days, lung hydroxyproline (HP) content increased significantly in mice treated with vehicle; in contrast, lung HP did not increase significantly compared to naïve controls in mice treated with GHRH-R antagonist. GHRH-R antagonist increased basal and maximal oxygen consumption of cultured lung fibroblasts. Multiple genes related to chemotaxis, IL-1, chemokines, regulation of inflammation, and extracellular signal–regulated kinases (ERK) were upregulated in lungs of mice treated with bleomycin and MIA-602. MIA-602 also prominently suppressed multiple genes related to the cellular immune response including those for T-cell differentiation, receptor signaling, activation, and cytokine production.ConclusionsMIA-602 reduced lung inflammation and fibrosis due to bleomycin. Multiple genes related to immune response and T-cell functions were downregulated, supporting the view that MIA-602 can modulate the cellular immune response to bleomycin lung injury.

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Growth hormone-releasing hormone receptor mediates cytokine production in ciliary and iris epithelial cells during LPS-induced ocular inflammation

Cited by 19 publications

References 21 publications

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

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

GHRH antagonists support lung endothelial barrier function

Growth Hormone-Releasing Hormone Receptor Antagonist Modulates Lung Inflammation and Fibrosis due to Bleomycin

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