PDE4 inhibitor apremilast ameliorates TNBS-induced irritable bowel syndrome in mice by activating the Nrf-2 signaling pathway in enteric glial cells

Abstract

Enteric glial cells (EGCs) play an important role in the pathogenesis of irritable bowel syndrome (IBS). Phosphodiesterase-4 (PDE4) functions as a catalyzing enzyme targeting hydrolyzation of intracellular cyclic adenosine monophosphate (cAMP). Increased PDE4 activity promotes excessive production of pro-inflammatory cytokines and chemokines in various immune and epithelial cells, exacerbating immune cell activation and infiltration in inflamed tissues, inhibition of PDE4 has been proven to be an important strategy for inflammatory and autoimmune diseases. In this study we investigated the pathological role of PDE4 and the therapeutic effects of a PDE4 inhibitor apremilast in IBS. 2,4,6-Trinitrobenzenesulfonic acid (TNBS)-induced IBS model was established in mice, the mice were treated with apremilast (50 mg/kg, i.g.) for 7 days. After treatment, the intestinal motility and visceral sensitivity were assessed. At the end of the study, the mice were euthanized and the blood and colon tissues were collected for analyses. We showed that apremilast treatment significantly ameliorated IBS symptoms in the mice, evidenced by improvement on delayed intestinal motility and visceral hypersensitivity. We found that EGCs were activated in the colon of IBS mice. We then demonstrated that apremilast (10 μM) significantly suppressed TNF-α/IFN-γ stimulated activation of rat EGC cell line CRL-2690 and primary EGCs in vitro, as well as the secretion of EGCs-derived pain mediators and inflammatory factors while ameliorating oxidative stress. These effects depended on the activation of the nuclear factor erythroid 2-related factor 2 (Nrf-2) signaling pathway, which was validated in Nrf-2 knockout EGCs. These results suggest that inhibition of PDE4 by apremilast suppresses EGCs activation by activating the Nrf-2 signaling pathway, leading to decreased expression of pain mediators and inflammatory factors while ameliorating oxidative stress, ultimately alleviating IBS.

Keywords: Nrf-2 signaling pathway; apremilast; enteric glial cell; irritable bowel syndrome; oxidative stress; phosphodiesterase-4.