Related Experiment Videos
Arsenic trioxide reduces 2,4,6-trinitrobenzene sulfonic acid-induced murine colitis via nuclear factor-κB
Monique Singer1, Germain Trugnan, Mounira K Chelbi-Alix
1INSERM U538, UPMC, UMRS 538, Faculty of Medicine Pierre et Marie Curie, Saint Antoine, Paris, France.
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.
Insights
Arsenic trioxide effectively treats inflammatory bowel diseases (IBDs) by reducing inflammation and promoting apoptosis in immune cells. This study suggests its therapeutic potential for conditions like Crohn's disease.
Area of Science:
- Immunology
- Pharmacology
- Gastroenterology
Background:
- Inflammatory bowel diseases (IBDs), including Crohn's disease, lack effective treatments and involve autoimmune and inflammatory processes.
- Arsenic trioxide (As(2)O(3)) is an established anti-cancer agent with known efficacy against autoimmune and inflammatory conditions in MRL/lpr mice.
Purpose of the Study:
- To investigate the potential therapeutic effects of arsenic trioxide (As(2)O(3)) on inflammatory bowel diseases (IBDs).
- To elucidate the molecular mechanisms underlying As(2)O(3)'s anti-inflammatory actions in a murine model of colitis.
Main Methods:
- Induction of colitis in mice using 2,4,6-trinitrobenzene sulfonic acid.
- Administration of arsenic trioxide (As(2)O(3)) in preventive and curative settings.
- Assessment of macroscopic and microscopic colitis scores, survival rates, NF-κB activity, cytokine gene expression, and neutrophil-related markers (KC, iNOS, MPO).
- Evaluation of procaspase-3 and caspase-3 activation to assess apoptosis.
Main Results:
- Arsenic trioxide (As(2)O(3)) significantly reduced colitis severity and improved survival in mice.
- As(2)O(3) inhibited NF-κB activation and decreased pro-inflammatory cytokine gene expression (TNF-α, IL-1β, IL-12, IL-17, IL-18, IL-23).
- As(2)O(3) reduced neutrophil infiltration and activation markers (KC, iNOS, MPO) and induced caspase-3 activation, suggesting apoptosis of inflamed cells.
Conclusions:
- Arsenic trioxide (As(2)O(3)) exhibits potent anti-inflammatory effects in a murine model of colitis.
- The therapeutic action of As(2)O(3) involves the inhibition of NF-κB and the induction of apoptosis via caspase-3 activation.
- As(2)O(3) demonstrates significant therapeutic potential for treating Crohn's disease and other severe IBDs.
