The new low calcemic vitamin D analog 22-ene-25-oxa-vitamin D prominently ameliorates T helper cell type 1-mediated colitis in mice.
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.
Daniel
Carolin
C
1st Department of Internal Medicine, Division of Gastroenterology and Clinical Nutrition, Johann Wolfgang Goethe University, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany.
Radeke
Heinfried H
HH
Sartory
Nico A
NA
Zahn
Nadine
N
Zuegel
Ulrich
U
Steinmeyer
Andreas
A
Stein
Jürgen
J
D000818:Animals; D002117:Calcitriol / Q000627:therapeutic use; D002118:Calcium / Q000097:blood; D003092:Colitis / Q000188:drug therapy*; D003404:Creatinine / Q000097:blood; D016753:Interleukin-10 / Q000096:biosynthesis; D015847:Interleukin-4 / Q000096:biosynthesis; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018167:Receptors, Calcitriol / Q000737:chemistry / Q000378:metabolism; D018417:Th1 Cells / Q000276:immunology*; D014302:Trinitrobenzenesulfonic Acid / Q000633:toxicity; D014807:Vitamin D / Q000031:analogs & derivatives* / Q000627:therapeutic use
C503158:22-ene-25-oxavitamin D; D018167:Receptors, Calcitriol; D016753:Interleukin-10; D014807:Vitamin D; D015847:Interleukin-4; D014302:Trinitrobenzenesulfonic Acid; D003404:Creatinine; D002117:Calcitriol; D002118:Calcium