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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on October 2, 2007; DOI: 10.1124/jpet.107.127209

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Received for publication June 14, 2007.
Revised September 27, 2007.
Accepted for publication September 28, 2007.

Immune modulatory treatment of TNBS colitis with calcitriol is associated with a change of a Th1/Th17 to a Th2 and regulatory T cell profile

Carolin Daniel 1, Nico A Sartory 2, Nadine Zahn 3, Heinfried H Radeke 4, Jurgen M Stein 2*

1 First Department of Internal Medicine, pharmazentrum, JWG University Frankfurt am Main 2 First Department of Internal Medicine Johann Wolfgang Goethe University 3 First Department of Internal Medicine JWG University Frankfurt am Main 4 pharmazentrum JWG University Frankfurt

* Address correspondence to: E-mail: j.stein{at}zafes.de

Abstract

A number of recent studies testify that calcitriol alone or in combination with corticosteroids exerts strong immunomodulatory activity. As a new approach we evaluated the pro-tolerogenic potential of calcitriol and dexamethasone in acute Th1-mediated colitis in mice. A rectal enema of TNBS [100 mg/kg] was applied to Balb/c mice. Calcitriol and/or dexamethasone were administered i.p. from day 0-3 or from day 3-5 following the instillation of the haptenating agent. Assessment of colitis severity was performed daily. Colon tissue was analyzed macroscopically and microscopically, myeloperoxidase activity, as well as cytokine levels (TNF-{alpha}, IFN-{gamma}, IL-12p70, IL-1{beta}, IL-10, IL-4) were determined by ELISA, T-bet, GATA3, Foxp3, CTLA4, IL-23p19 and IL-17 expression by immunoblot analysis. The combination of these steroids most effectively reduced the clinical and histopathologic severity of TNBS colitis. Th1-related parameters were down- while 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-{beta}, FoxP3 and CTLA4. Furthermore, analysis of dendritic cell mediators responsible for a pro-inflammatory 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 the 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.


Key words: Th1/Th2/Th17 profile, calcitriol, colitis, dexamethasone, mice, regulatory T cells




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