Cholera toxin subunit B inhibits IL-12 and IFN-  production and signaling in experimental colitis and Crohn's disease

Abstract

Background and aims: Cholera toxin B subunit (CT-B) is a powerful modulator of immune responses. The authors have previously demonstrated that oral administration of recombinant CT-B (rCT-B) is able to prevent and cure the Crohn's disease (CD)-like trinitrobenzene sulfonic acid (TNBS) mediated colitis. In this study they extended their observations and examined if rCT-B interferes with the molecular signaling underlying the Th1 type response both in TNBS colitis and in ex vivo human CD explants. Methods: TNBS treated mice were fed with rCT-B, and IFN-c and IL-12 production by colonic lamina propria mononuclear cells (LPMC) was examined by ELISA. In vitro culture of mucosal explants from CD patients and non-inflammatory bowel disease controls, pre-incubated with rCT-B, were examined for IFNc and IL-12 production by ELISA and semiquantitative reverse transcription polymerase chain reactions. STAT-1, -4, -6 activation and T-bet expression were examined following rCT-B treatment by western blotting both in TNBS treated mice and in human mucosal explants. Conclusions: These studies indicate that CT-B inhibits mucosal Th1 cell signaling and suggest that rCT-B may be a promising candidate for CD therapy.

Cholera-Toxin Suppresses Carcinogenesis in a Mouse Model of Inflammation-Driven Sporadic Colon Cancer

“…The powerful adjuvant, immunomodulatory and oral tolerance inducing properties of CT and its B subunit have been shown to prevent experimentally induced autoimmune diseases and allergies in various preclinical rodent models (17,(32)(33)(34). CT has been reported to modulate the expression of both Th1 and Th2 cytokines (16,17,19,20,22). Although the results of different studies vary, most researchers agree that CT downregulates the proinflammatory cytokines IL-12, IL-6 and TNF-α, and upregulates the anti-inflammatory cytokines IL-10 and Tgf-β (16,17,19,22).…”

“…For that, CT is considered an attractive component of oral tolerance-based immunotherapy schemes for the treatment of immune-related disorders (15)(16)(17). CT activates antigen-presenting cells (16,(18)(19)(20)(21), induces Tregs and expands their population (16,17,19), affects the expression of cytokines and modulates both Th1 and Th2 immune responses (16,17,20,22). Interestingly, these immune events have been shown to affect carcinogenic processes (12).…”

A plant-made cholera toxin B subunit enhances mucosal wound healing and protects against ulcerative colitis and colon cancer.

“…Accordingly, studies are currently underway to elucidate the mechanism and the potential contribution of CTBp-induced colonic immune cell profile in the context of mucosal healing. While CTB's mucosal healing potential has not been previously reported, past studies have shown that the protein can blunt intestinal inflammation of Crohn's disease in a mouse model and in a small-scale clinical trial (73,74). In the mouse model, CTB inhibited the production of IFNγ and IL-12 in colon lamina propria mononuclear cells, which was reproduced in human Crohn's disease explant tissues (73).…”

“…While CTB's mucosal healing potential has not been previously reported, past studies have shown that the protein can blunt intestinal inflammation of Crohn's disease in a mouse model and in a small-scale clinical trial (73,74). In the mouse model, CTB inhibited the production of IFNγ and IL-12 in colon lamina propria mononuclear cells, which was reproduced in human Crohn's disease explant tissues (73). In the present study, hallmarks of anti-inflammatory effects (decreased body weight loss, inflammation scores and inflammatory cytokine mRNA/protein levels) were noted in the DSS colitis model after CTBp administration (Chapter 3); similar to the findings from the Crohn's disease experiments.…”

“…As discussed in Chapter 1, CTB was shown to protect against trinitrobenzene sulfonic acid (TNBS)-induced colitis in mice and reduced inflammatory cytokine production in human Crohn's disease explants (72,73). In IBD is composed of two main disease categories, Crohn's disease and ulcerative colitis, which have similarities pathologically but some important differences remain (see reviews (115)(116)(117)).…”