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Effects of Retinoids in Mouse Models of Colitis: Benefit or Danger to the Gastrointestinal Tract?

Frey-Wagner, Isabelle PhD; Fischbeck, Anne PhD; Cee, Alexandra MSc; Leonardi, Irina MSc; Gruber, Sven; Becker, Eugenia MSc; Atrott, Kirstin; Lang, Silvia; Rogler, Gerhard MD, PhD

doi: 10.1097/MIB.0b013e31829cf1fc
Original Basic Science Articles

Background: In vitro and in vivo data have shown that retinoid treatment promotes an anti-inflammatory milieu with few adverse effects toward the gastrointestinal tract. The in vivo studies reported here further evaluate retinoid effects in 2 mouse models of inflammatory bowel disease.

Method: Chronic dextran sulfate sodium colitis was induced in age- and weight-matched C57Bl/6 mice by 4 cycles of dextran sulfate sodium administration (6–8 animals/group). At cycle 4, animals were administered 13-cis-retinoic acid (isotretinoin, 30 mg/kg) or vehicle (oral gavage) or 4-oxo-13-cis-retinoic acid (15 mg/kg, intraperitoneal) daily. T-cell transfer colitis was induced in CB17 SCID mice by transfer of naive CD4+CD62L+ T cells and treated by transfer of regulatory CD4+CD25+ T cells (4–6 animals/group); isolated from BALB/c mice after treatment with isotretinoin or vehicle, as above, for 2 weeks. Assessments included endoscopic and histological scores, myeloperoxidase activity, serum cytokines, and plasma isotretinoin levels.

Results: Retinoid-treated animals with colitis showed comparable changes in myeloperoxidase activity, and endoscopic and histological scores, versus untreated animals with colitis. Modest and comparable changes were seen in body weight and colon length in animals injected with naive T cells from isotretinoin-treated donors versus those injected with T cells from vehicle-treated donors. Retinoid treatment was consistently associated with lower interleukin-12 levels, which, after the transfer of naive T cells from isotretinoin-treated donors, supported isotretinoin-mediated predisposition of naive T cells toward reduced proinflammatory cytokine expression. Colitis had no effect on isotretinoin exposure.

Conclusions: Retinoids attenuate the proinflammatory cytokine response in vivo, with only modest effects on body weight and parameters of gastrointestinal morphology.

Article first published online 30 July 2013

Division of Gastroenterology and Hepatology, Department of Internal Medicine, University Hospital of Zurich, Zurich, Switzerland.

Reprints: Gerhard Rogler, MD, PhD, Division of Gastroenterology and Hepatology, Department of Internal Medicine, University Hospital of Zurich, Rämistrasse 100, CH-8091 Zurich, Switzerland (e-mail: gerhard.rogler@usz.ch).

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s Web site (www.ibdjournal.org).

The first two authors have contributed equally to this work.

Author disclosures are available in the Acknowledgments.

Received March 13, 2013

Accepted May 21, 2013

© Crohn's & Colitis Foundation of America, Inc.
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