Arsenic trioxide reduces 2,4,6-trinitrobenzene sulfonic acid-induced murine colitis via nuclear factor-κB down-regulation and caspase-3 activation

Abstract

Arsenic trioxide, As₂O₃, already used in human anti-cancer therapy, is also an efficient agent against the autoimmune and inflammatory diseases developed in MRL/lpr mice. Inflammatory bowel diseases (IBDs), notably Crohn’s disease, which remain without efficient treatment, display autoimmune and inflammatory components. We, therefore, hypothesized that As₂O₃ may be active on IBDs. Using the 2,4,6-trinitrobenzene sulfonic acid-induced murine model of colitis, we demonstrate that As₂O₃ used either in a preventive or a curative mode markedly reduced the induced colitis as assessed by macroscopic and microscopic scores, leading to prolonged mice survival. In addition, As₂O₃ was able to inhibit NF-κB expression and DNA-binding in colon extracts leading to decreased cytokine gene expression (i.e. tumor necrosis factor-α, interleukin(IL)-1β, IL-12, IL-17, IL-18, and IL-23). Interestingly, As₂O₃ also reduced keratinocyte-derived chemokine (KC), inducible nitric oxide synthase (iNOS) mRNA levels, and myeloperoxidase (MPO) protein expression suggesting an impairment of neutrophils. This was associated with a marked increase of procaspase-3 and induced caspase-3 activation. This caspase-3 co-localized with MPO in the remaining neutrophils suggesting that As₂O₃ might have eliminated inflamed cells probably by inducing their apoptosis. These results assessed the potent anti-inflammatory effect of As₂O₃, that targets both NF-κB and caspase-3 pathways, and suggests a therapeutic potential for Crohn’s disease and other severe IBDs.

Keywords

IBD inflammation therapy autoimmune disease apoptosis

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