Article Text
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-γ 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 IFN-γ 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.
Results: rCT-B significantly reduced IL-12 and IFN-γ secretion by LPMC from TNBS treated mice. Consistent with this, rCT-B inhibited both STAT-4 and STAT-1 activation and downregulated T-bet expression. Inhibition of Th1 signaling by CT-B associated with no change in IL-4 synthesis and expression of active STAT-6 indicating that rCT-B does not enhance Th2 cell responses. Moreover, in vitro treatment of CD mucosal explants with rCT-B resulted in reduced secretion of IL-12/IFN-γ and inhibition of STAT-4/STAT-1 activation and T-bet expression.
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.
- CD, Crohn’s disease
- CT, cholera toxin
- IBD, inflammatory bowel disease
- LPMC, lamina propria mononuclear cells
- TNBS, trinitrobenzene sulfonic acid
- UC, ulcerative colitis
- Crohn’s disease
- cholera toxin B subunit
- interleukin-12
- interferon-γ
- transcription factors
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Footnotes
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Published online first 16 August 2005
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This work was supported by grants from the Istituto Superiore di Sanità (99F and 2AEI to EC and to MB).
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Competing interests: none declared.