Immune Modulatory Treatment of Trinitrobenzene Sulfonic Acid Colitis with Calcitriol Is Associated with a Change of a T Helper (Th) 1/Th17 to a Th2 and Regulatory T Cell Profile

Abstract

A number of recent studies testify that calcitriol alone or in combination with corticosteroids exerts strong immune modulatory activity. As a new approach, we evaluated the protolerogenic potential of calcitriol and dexamethasone in acute T helper (Th)1-mediated colitis in mice. A rectal enema of trinitrobenzene sulfonic acid (TNBS) (100 mg/kg) was applied to BALB/c mice. Calcitriol and/or dexamethasone were administered i.p. from days 0 to 3 or 3 to 5 following the instillation of the haptenating agent. Assessment of colitis severity was performed daily. Colon tissue was analyzed macroscopically and microscopically, and myeloperoxidase activity, as well as cytokine levels [tumor necrosis factor-␣, interferon-␥, interleukin (IL)-12p70, IL-1␤, IL-10, IL-4] were determined by enzymelinked immunosorbent assay, T-bet, GATA family of transcription factors 3, a Th2 master regulator (GATA3), Foxp3, cytotoxic T-lymphocyte-associated antigen 4 (CTLA4), IL-23p19 and IL-17 expression by immunoblot analysis. The combination of the steroids most effectively reduced the clinical and histopathologic severity of TNBS colitis. Th1-related parameters were down-regulated, whereas Th2 markers like IL-4 and GATA3 were up-regulated. Apart from known steroid effects, calcitriol in particular promoted regulatory T cell profiles as indicated by a marked increase of IL-10, TGF␤, FoxP3, and CTLA4. Furthermore, analysis of dendritic cell mediators responsible for a proinflammatory differentiation of T cells revealed a significant reduction of IL-12p70 and IL23p19 as well as IL-6 and IL-17. Thus, our data support a rationale for a steroid-sparing, clinical application of calcitriol derivatives in inflammatory bowel disease. Furthermore they suggest that early markers of inflammatory dendritic cell and Th17 differentiation qualify as new target molecules for both calcitriol and highly selective immune-modulating vitamin D analogs.Calcitriol has been identified in a number of studies as a prominent negative regulator of T helper (Th1)-type immune responses, whereas Th2 responses are not affected or even augmented as indicated by an induction of T1/ST2 (Schmitz et al., 2005;Wang et al., 2005). Although these effects have been preferentially explained by direct effects on lymphocytes, subsequent studies clearly supported a role of calcitriol in modulating monocyte differentiation or dendritic cell (DC) maturation (Griffin et al., 2003). Calcitriol clearly reduced the transition of the innate immune stimulation to an adaptive inflammatory immune response by interfering with signal transducers and activators of transcription, interferon regulatory factor 1/4, and possibly with the molecular elements involved in cross-presentation (Penna and Adorini, 2000;Muthian et al., 2006). With respect to myeloid DC development, the phenotype of calcitriol-conditioned DC reflects an immature status with poor capacity to induce antigen-specific T cell proliferation and a tendency to promote tolerance in vivo (Mellman and Steinman, 2001).The immunoregu...

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Blockade of complement activation product C5a activity using specific antibody attenuates intestinal damage in trinitrobenzene sulfonic acid induced model of colitis

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