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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on August 16, 2006; DOI: 10.1124/jpet.106.107599

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Received for publication May 16, 2006.
Revised July 28, 2006.
Accepted for publication August 10, 2006.

The new low calcemic vitamin D analog 22-ene-25-oxa-vitamin D prominently ameliorates Th1-mediated colitis in mice

Carolin Daniel 1, Heinfried H Radeke 2, Nico A Sartory 1, Nadine Zahn 1, Ulrich Zuegel 3, Andreas Steinmeyer 3, Juergen M Stein 1*

1 First Department of Internal Medicine JWG University Frankfurt am Main 2 pharmazentrum Frankfurt JWG University Frankfurt am Main 3 Schering Corporate Research Berlin

* Address correspondence to: E-mail: j.stein{at}em.uni-frankfurt.de

Abstract

In addition to its well-defined role as key regulator of calcium and bone metabolism, 1,25-dihydroxyvitamin D3 (calcitriol) has been established as a potent modulator of immune cell function. Still, due to the hypercalcemic toxicity occurring after systemic application of the parent compound its clinical application as an immunosuppressant has been hampered. Recently, we described 22-ene-25-oxa vitamin D (ZK156979) as a representative of a novel class of low calcemic vitamin D analogs with a well preserved immunosuppressive activity in vitro. Here, in vivo a colitis was induced by applying a rectal enema of TNBS to male Balb/c mice, and calcitriol [0.2 µg/kg] or ZK156979 [0.1 to 2.0 µg/kg] was given intraperitoneally from day 0-3 or 3-5. Body mass and clinical activity score of colitis were recorded daily. Colon tissue was analyzed macroscopically and microscopically, myeloperoxidase activity as well as cytokine levels (TNF-{alpha}, IFN-{gamma}, IL-10, IL-4) were determined by ELISA, T-bet expression by immunoblot analysis. We found that treatment with ZK156979 clearly reduced the severity of TNBS-colitis without exhibiting calcemic effects. Both, early and late treatment abrogated body weight loss, diarrhea, and macroscopic intestinal inflammation with a potency comparable to calcitriol. The therapeutic effect of ZK156979 was accompanied by a down-regulation of MPO-activity, TNF-{alpha}, IFN-{gamma} and T-bet expression, while local tissue IL-10 and IL-4 protein levels increased. To conclude, our data provide first clear evidence that ZK156979 exhibits a beneficial prophylactic as well as therapeutic profile in Th1-like experimental colitis offering new therapeutic options for the treatment of human inflammatory bowel diseases.


Key words: Calcitriol, IBD, TNBS colitis, Th1/Th2 profile, Vitamin D analogs, immunomodulation


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