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Antagonist of GH-releasing hormone receptors alleviates experimental ocular inflammation.

ABSTRACT: Disruptions in immunity and occurrence of inflammation cause many eye diseases. The growth hormone-releasing hormone-growth hormone-insulin-like growth factor-1 (GHRH-GH-IGF1) axis exerts regulatory effects on the immune system. Its involvement in ocular inflammation remains to be investigated. Here we studied this signaling in endotoxin-induced uveitis (EIU) generated by LPS. The increase in GHRH receptor (GHRH-R) protein levels was parallel to the increase in mRNA levels of pituitary-specific transcription factor-1, GHRH-R splice variant 1, GHRH, and GH following LPS insult. Elevation of GHRH-R and GH receptor was localized on the epithelium of the iris and ciliary body, and GHRH-R was confined to the infiltrating macrophages and leukocytes in aqueous humor but not to those in stroma. Treatment with GHRH-R antagonist decreased LPS-stimulated surges of GH and IGF1 in aqueous humor and alleviated inflammation by reducing the infiltration of macrophages and leukocytes and the production of TNF-?, IL-1?, and monocyte chemotactic protein-1. Our results indicate that inflammation in the iris and ciliary body involves the activation of GHRH signaling, which affects the recruitment of immune cells and the production of proinflammatory mediators that contribute to EIU pathogenesis. Moreover, the results suggest that GHRH-R antagonists are potential therapeutic agents for the treatment of acute ocular inflammation.

SUBMITTER: Qin YJ

PROVIDER: S-EPMC4280596 | biostudies-literature | 2014 Dec

REPOSITORIES: biostudies-literature

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Antagonist of GH-releasing hormone receptors alleviates experimental ocular inflammation.

Qin Yong Jie YJ Chan Sun On SO Chong Kelvin Kam Lung KK Li Benjamin Fuk Loi BF Ng Tsz Kin TK Yip Yolanda Wong Ying YW Chen Haoyu H Zhang Mingzhi M Block Norman L NL Cheung Herman S HS Schally Andrew V AV Pang Chi Pui CP

Proceedings of the National Academy of Sciences of the United States of America 20141208 51

Disruptions in immunity and occurrence of inflammation cause many eye diseases. The growth hormone-releasing hormone-growth hormone-insulin-like growth factor-1 (GHRH-GH-IGF1) axis exerts regulatory effects on the immune system. Its involvement in ocular inflammation remains to be investigated. Here we studied this signaling in endotoxin-induced uveitis (EIU) generated by LPS. The increase in GHRH receptor (GHRH-R) protein levels was parallel to the increase in mRNA levels of pituitary-specific ...[more]

PMID: 25489106

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Project description:It is known that growth hormone (GH) is expressed in immune cells, where it exerts immunomodulatory effects. However, the mechanisms of expression and release of GH in the immune system remain unclear. We analyzed the effect of growth hormone-releasing hormone (GHRH), thyrotropin-releasing hormone (TRH), ghrelin (GHRL), and somatostatin (SST) upon GH mRNA expression, intracellular and released GH, Ser133-phosphorylation of CREB (pCREBS133), intracellular Ca2+ levels, as well as B-cell activating factor (BAFF) mRNA expression in bursal B-lymphocytes (BBLs) cell cultures since several GH secretagogues, as well as their corresponding receptors (-R), are expressed in B-lymphocytes of several species. The expression of TRH/TRH-R, ghrelin/GHS-R1a, and SST/SST-Rs (Subtypes 1 to 5) was observed in BBLs by RT-PCR and immunocytochemistry (ICC), whereas GHRH/GHRH-R were absent in these cells. We found that TRH treatment significantly increased local GH mRNA expression and CREB phosphorylation. Conversely, SST decreased GH mRNA expression. Additionally, when added together, SST prevented TRH-induced GH mRNA expression, but no changes were observed in pCREBS133 levels. Furthermore, TRH stimulated GH release to the culture media, while SST increased the intracellular content of this hormone. Interestingly, SST inhibited TRH-induced GH release in a dose-dependent manner. The coaddition of TRH and SST decreased the intracellular content of GH. After 10 min. of incubation with either TRH or SST, the intracellular calcium levels significantly decreased, but they were increased at 60 min. However, the combined treatment with both peptides maintained the Ca2+ levels reduced up to 60-min. of incubation. On the other hand, BAFF cytokine mRNA expression was significantly increased by TRH administration. Altogether, our results suggest that TRH and SST are implicated in the regulation of GH expression and release in BBL cultures, which also involve changes in pCREBS133 and intracellular Ca2+ concentration. It is likely that TRH, SST, and GH exert autocrine/paracrine immunomodulatory actions and participate in the maturation of chicken BBLs.

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Antagonist of GH-releasing hormone receptors alleviates experimental ocular inflammation.

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Antagonist of GH-releasing hormone receptors alleviates experimental ocular inflammation.

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