Ghrelin Inhibits the Differentiation of T Helper 17 Cells through mTOR/STAT3 Signaling Pathway

Abstract

Enhanced activity of interleukin 17 (IL-17) producing T helper 17 (Th17) cells plays an important role in autoimmune and inflammatory diseases. Significant loss of body weight and appetite is associated with chronic inflammation and immune activation, suggesting the cross talk between immune and neuroendocrine systems. Ghrelin has been shown to regulate the organism immune function. However, the effects of ghrelin on the differentiation of Th17 cells remain elusive. In the present study, we observed the enhanced differentiation of Th17 cells in spleens of growth hormone secretagogue receptor 1a (GHSR1a)-/- mice. Treatment of ghrelin repressed Th17 cell differentiation in a time- and concentration-dependent manner. Phosphorylation of mammalian target of rapamycin (mTOR) and signal transducer and activator of transcription 3 (STAT3) was increased in the spleens of GHSR1a-/- mice. Activation of mTOR signaling by injection of Cre-expressiong adenovirus into tuberous sclerosis complex 1 (TSC1) loxp/loxp mice increased the differentiation of Th17 cells in spleen, which was associated with an increment in the phosphorylation of STAT3. Activation of mTOR signaling by leucine or overexpression of p70 ribosome protein subunit 6 kinase 1 (S6K1) activated mTOR signaling in isolated T cells, while reversed the ghrelin-induced inhibition of iTh17 cell differentiation. In conclusion, mTOR mediates the inhibitory effect of ghrelin on the differentiation of Th17 cells by interacting with STAT3.

Autophagy impacts on oxaliplatin-induced hepatocarcinoma apoptosis via the IL-17/IL-17R-JAK2/STAT3 signaling pathway

“…To delineate the potential mechanism underlying IL-17/IL-17R-induced autophagy, the activation status of JAK2 and STAT3 under the interference of IL-17/IL-17R was observed. It was found that IL-17/IL-17R increased the phosphorylation of JAK2 and STAT3, which was consistent with the fact that STAT3 controls Th17 cell differentiation (54). Previous studies have shown that the PI3K signaling pathway has a crucial role in autophagy (55)(56)(57).…”

Gastric Helicobacter pylori Infection Affects Local and Distant Microbial Populations and Host Responses

“…The differential ghrelin physiology in control and H. pylori -infected mice that we observed, consistent with prior studies (Bercik et al, 2009), provides further evidence of the systemic effects of gastric H. pylori. The anti-inflammatory properties of ghrelin, inhibiting Th17 cell differentiation (Xu et al, 2015), might partially explain why when levels are high (3-months), pulmonary Th17 populations are not significantly elevated. This hormonal interaction may provide H. pylori with additional means for evading host immune responses.…”

Ghrelin receptor modulates T helper cells during intestinal inflammation

“…Our data are in agreement with recent literature reporting a specific effect of ghrelin on both Th1 and Th17 expansion at steady state and during systemic inflammation in mice. 11,42,43 In particular, potent therapeutic effects of ghrelin have been recently described in a mouse model of EAE, in which autoimmune reaction is involved in the disease development. Souza-Moreira et al have shown that systemic treatment with ghrelin, after the disease onset, reduced clinical severity of EAE via specifically acting on the expansion of encephalitogenic Th1 and Th17.…”