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, As(2)O(3), 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 As(2)O( 3) may be active on IBDs. Using the 2,4,6-trinitrobenzene sulfonic acid-induced murine model of colitis, we demonstrate that As(2)O(3) 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, As(2)O(3) 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, As(2)O(3) 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 As(2)O( 3) might have eliminated inflamed cells probably by inducing their apoptosis. These results assessed the potent anti-inflammatory effect of As(2)O( 3), that targets both NF-κB and caspase-3 pathways, and suggests a therapeutic potential for Crohn's disease and other severe IBDs.