Tacrolimus Up-regulates Expression of TGFβ Receptor Type IIviaERK, 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. Inflammatory bowel diseases (IBDs), including Crohn's disease and ulcerative colitis (UC), are refractory chronic diseases with repeated relapse and remission cycles, which are mediated by multiple immunological dysfunctions (1). Transforming growth factor β (TGFβ) is a multifunctional cytokine that regulates cellular processes, including differentiation, proliferation, apoptosis, and extracellular matrix production, depending on the tissue and signal intensity (2). Deregulation of the TGFβ signaling pathway is one of the known immunological dysfunctions in IBDs. Loss of TGFβ signaling is involved in colitis development in experimental models and IBD pathogenesis in humans (3, 4).A report showed that selective loss of TGFβ signaling resulted in intestinal inflammation (5). Moreover, we reported that loss of TGFβ signaling increased apoptosis of epithelial cells (6) and cyclosporine, a calcineurin inhibitor, ameliorated dextran sulfate sodium (DSS)-induced colitis in mice by upregulating TGFβ expression in colonic tissue and activating TGFβ signaling in intestinal epithelial cells (IECs) (7). TGFβ signaling in IECs plays a key role in maintaining the gut's barrier function via regulation of epithelial cell apoptosis (8).TGFβ signaling in IECs is regulated by various signaling proteins such as protein kinase C, phospholipase C, protein phosphatase 1, RAS, several mitogen-activated protein kinase (MAPK) superfamily members, and mothers against decapentaplegic (SMAD) superfamily members (9). Each signaling cascade is known to intersect intricately with others and the intersections have not been fully elucidated. Identification of signaling pathways involved in intestinal epithelial injury will contribute to the discovery of new therapeutic approaches for preventing epithelial destruction.Like other calcineurin inhibitors, tacrolimus is a potent immunomodulator that blocks T-cell activation (10).

Tumorigenic role of tacrolimus through mTORC1/C2 activation in post-transplant renal cell carcinomas

“…In addition to its main CNI effect, TAC is also capable of stimulating the expression of TGF-β in a dose-dependent manner through the ERK pathway [ 45 , 46 ]. Activated TGF-β could stimulate various downstream pathways, including the main/canonic (SMAD) and alternative pathways (MAPK, ERK1/2, PI3K/AKT and JNK), contributing to EMT promotion, ECM accumulation, immune invasion and tumorigenesis [ 47 , 48 ].…”

Combination of Lactobacillus plantarum improves the effects of tacrolimus on colitis in a mouse model

“…Recently, tacrolimus has been recommended for the treatment of refractory IBD, showing efficacy in both human and animal colitis ( Baumgart et al., 2006 ; Yoshino et al., 2010 ). In addition to the traditional calcineurin-dependent inhibitory effect on T cells, several studies have reported that the mechanism of tacrolimus-ameliorated colitis might be related to the suppression of activated macrophages ( Yoshino et al., 2010 ; Cai et al., 2021 ), the restriction of dendritic cell migration and the subsequent differentiation of CD4+ T cells to Th1 and Th17 cells ( Regmi et al., 2019 ), as well as protection against apoptosis-mediated intestinal epithelial injury ( Satake et al., 2022 ). In accordance with previous research, we found a significant alleviation of DSS-induced colitis by tacrolimus treatment.…”