Arsenic trioxide reduces 2,4,6-trinitrobenzene sulfonic acid-induced murine colitis via nuclear factor-κB down-regulation and caspase-3 activation.
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.
Singer
Monique
M
INSERM U538, UPMC, UMRS 538, Faculty of Medicine Pierre et Marie Curie, Saint Antoine, Paris, France.
Trugnan
Germain
G
Chelbi-Alix
Mounira K
MK
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage* / Q000009:adverse effects; D017209:Apoptosis / Q000187:drug effects; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000008:administration & dosage* / Q000009:adverse effects; D053148:Caspase 3 / Q000378:metabolism; D003092:Colitis / Q000139:chemically induced / Q000188:drug therapy* / Q000276:immunology; D003106:Colon / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D003424:Crohn Disease / Q000188:drug therapy* / Q000276:immunology; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D010087:Oxides / Q000008:administration & dosage* / Q000009:adverse effects; D009195:Peroxidase / Q000235:genetics / Q000378:metabolism; D014302:Trinitrobenzenesulfonic Acid / Q000008:administration & dosage
D000893:Anti-Inflammatory Agents; D001152:Arsenicals; D016207:Cytokines; D016328:NF-kappa B; D010087:Oxides; D014302:Trinitrobenzenesulfonic Acid; D009195:Peroxidase; D052247:Nitric Oxide Synthase Type II; D053148:Caspase 3; D000077237:Arsenic Trioxide