In addition to its well defined role as a key regulator of
calcium and bone metabolism,
1,25-dihydroxyvitamin D(3) (
calcitriol) has been established as a potent modulator of immune cell function. Still, because of 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 well preserved immunosuppressive activity in vitro. Here, in vivo
colitis was induced by applying a rectal
enema of
2,4,6-trinitrobenzene sulfonic acid (TNBS) to male BALB/c mice, and
calcitriol (0.2 microg/kg) or
ZK156979 (0.1-2.0 microg/kg) was given i.p. from days 0 to 3 or 3 to 5. Body mass and clinical activity score of
colitis were recorded daily. Colon tissue was analyzed macroscopically and microscopically,
myeloperoxidase activity and
cytokine levels [
tumor necrosis factor (
TNF)-alpha,
interferon (IFN)-gamma,
interleukin (IL)-10, and IL-4] were determined by
enzyme-linked
immunosorbent assay, and T-box
transcription factor (T-bet) expression was determined by immunoblot analysis. We found that treatment with
ZK156979 clearly reduced the severity of TNBS-induced
colitis without exhibiting calcemic effects. Both early and late treatment abrogated
body weight loss,
diarrhea, and macroscopic intestinal
inflammation with a potency comparable with that of
calcitriol. The
therapeutic effect of
ZK156979 was accompanied by a down-regulation of
myeloperoxidase activity,
TNF-alpha, IFN-gamma, and T-bet expression decreased, whereas local tissue
IL-10 and
IL-4 protein levels increased. To conclude, our data provide the first clear evidence that
ZK156979 exhibits a beneficial prophylactic as well as therapeutic profile in T helper cell type 1-like experimental
colitis, offering new therapeutic options for the treatment of human
inflammatory bowel diseases.