Growth hormone releasing hormone signaling promotes Th17 cell differentiation and autoimmune inflammation

Abstract

Dysregulation of Th17 cell differentiation and pathogenicity contributes to multiple autoimmune and inflammatory diseases. Previously growth hormone releasing hormone receptor (GHRH-R) deficient mice have been reported to be less susceptible to the induction of experimental autoimmune encephalomyelitis. Here, we show GHRH-R is an important regulator of Th17 cell differentiation in Th17 cell-mediated ocular and neural inflammation. We find that GHRH-R is not expressed in naïve CD4+ T cells, while its expression is induced throughout Th17 cell differentiation in vitro. Mechanistically, GHRH-R activates the JAK-STAT3 pathway, increases the phosphorylation of STAT3, enhances both non-pathogenic and pathogenic Th17 cell differentiation and promotes the gene expression signatures of pathogenic Th17 cells. Enhancing this signaling by GHRH agonist promotes, while inhibiting this signaling by GHRH antagonist or GHRH-R deficiency reduces, Th17 cell differentiation in vitro and Th17 cell-mediated ocular and neural inflammation in vivo. Thus, GHRH-R signaling functions as a critical factor that regulates Th17 cell differentiation and Th17 cell-mediated autoimmune ocular and neural inflammation.

Protective Activities of Growth Hormone-Releasing Hormone Antagonists against Toxin-Induced Endothelial Injury

“…It has been suggested that there is a positive relationship between the plasma IGF-I levels and the chance of developing colorectal, breast, and prostate cancer. GHRHAnt oppose endothelial barrier dysfunction, induce the barrier enhancer P53, and activate UPR to support barrier integrity [4]. Pathways that are involved in the mediation of GHRH-related analogs in endothelial inflammation have been discussed previously [10].…”

“…GHRHAnt are peptides designed to alleviate the inflammatory and tumor-promoting effects of the GH/GHRH axis in human and animal tissues [2,3] and act-at least in part-by binding to the growth hormone-releasing hormone receptor and its splice variants. Those receptors are expressed in various tissues and endothelial cells [4][5][6][7][8], including BPAECs [9]. GHRHAnt were initially synthesized to suppress tumors in experimental models of malignancies.…”

Ceapin‐A7 potentiates lipopolysaccharide‐induced endothelial injury

“…GHRHAnt are anticancer and anti‐inflammatory compounds. [ 49,50 ] It was shown that they can activate UPR, and counteract endothelial hyperpermeability due to UPR suppression. [ 51 ] In addition, those antagonists suppress the production of inducible nitric oxide synthase (iNOS) and exert antioxidative effects.…”

Unfolded protein response suppression potentiates LPS-induced barrier dysfunction and inflammation in bovine pulmonary artery endothelial cells

“… 28 GHRH receptors are involved in inflammation, and GHRHAnt exert strong anti-inflammatory and anti-oxidative effects. 27 , 29 , 30 Those antagonists can inhibit bleomycin-induced fibrosis 31 and prevent LPS-induced bronchoalveolar lavage fluid (BALF) protein concentration in vivo , suggesting their protective effects against edema. 32 Hsp90 inhibitors exert similar activities, they can activate UPR, 23 , 24 and counteract the kifunensine (UPR suppressor)-induced lung endothelial dysfunction.…”