Inhibition Of The Activation Of Gamma Delta T17 Cells Through Ppar Gamma-Pten/Akt/Gsk3 Beta/Nfat Pathway Contributes To The Anti-Colitis Effect Of Madecassic Acid

Type-17 immune response, mediated mainly by IL-17, plays a critical role in ulcerative colitis. Previously, we showed that madecassic acid (MA), the main active ingredient of Centella asiatica herbs for anti-colitis effect, ameliorated dextran sulfate sodium (DSS)-induced mouse colitis through reducing the level of IL-17. Here, we explore the effect of MA on the activation of gamma delta T17 cells, an alternative source of IL-17 in colitis. In DSS-induced colitis mice, oral administration of MA decreased the number of gamma delta T17 cells and attenuated the inflammation in the colon, and the anti-colitis effect of MA was significantly counteracted by redundant gamma delta T17 cells, suggesting that the decrease in gamma delta T17 cells is important for the anti-colitis effect of MA. In vitro, MA could inhibit the activation but not the proliferation of gamma delta T17 cells at concentrations without evident cytotoxicity. Antibody microarray profiling showed that the inhibition of MA on the activation of gamma delta T17 cells involved PPAR gamma -PTEN/Akt/GSK3 beta /NFAT signals. In gamma delta T17 cells, MA could reduce the nuclear localization of NFATc1 through inhibiting Akt phosphorylation to promote GSK3 beta activation. Moreover, it was confirmed that MA inhibited the Akt/GSK3 beta /NFATc1 pathway and the activation of gamma delta T17 cells through activating PPAR gamma to increase PTEN expression and phosphorylation. The correlation between activation of PPAR gamma, decrease in gamma delta T17 cell number, and amelioration of colitis by MA was validated in mice with DSS-induced colitis. In summary, these findings reveal that MA inhibits the activation of gamma delta T17 cells through PPAR gamma -PTEN/Akt/GSK3 beta /NFAT pathway, which contributes to the amelioration of colitis.