Tacrolimus Up-regulates Expression of TGFβ Receptor Type II via ERK, Providing Protection Against Intestinal Epithelial Injury

Abstract

Background/aim: Transforming growth factor β (TGFβ) signaling plays a key role in modulating intestinal epithelial cell (IEC) homeostasis. The present study aimed to investigate the direct effect of tacrolimus on TGFβ signaling in IECs.

Materials and methods: The protective effects of tacrolimus, with or without anti-TGFβ antibody, in dextran sulfate sodium (DSS)-induced colitis were evaluated.

Results: Tacrolimus ameliorated IEC apoptosis-mediated mucosal destruction despite anti-TGFβ treatment. TGFβ receptor type II (TGFβ-RII), phosphor-SMAD family members 2/3, and phosphor-extracellular signal-regulated kinase (ERK) expression in IECs was enhanced in tacrolimus-treated mice, and these positive effects were maintained despite anti-TGFβ treatment. Moreover, tacrolimus induced TGFβ-RII up-regulation through ERK activation.

Conclusion: Our data indicate that tacrolimus directly activated TGFβ-SMAD signaling via the ERK pathway in IECs, thereby providing protection against apoptosis-mediated intestinal epithelial injury.

Keywords: ERK; SMAD2/3; Tacrolimus; intestinal epithelial cell; transforming growth factor β receptor.