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GASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

Oral Treatment with Recombinant Human Interleukin-11 Improves Mucosal Transport in the Colon of Human Leukocyte Antigen-B27 Transgenic Rats

Oklahoma Foundation for Digestive Research Basic Science Laboratories, Veterans Affairs Medical Center, Oklahoma City, Oklahoma (K.V., B.G.V.M.); and Discovery Research, Wyeth Research, Cambridge, Massachusetts (J.C.K.)

Recombinant human interleukin (IL)-11 is a pleiotropic cytokine with anti-inflammatory activity. The objective of the study was to investigate whether oral treatment with rhIL-11 improves colonic epithelial dysfunction in the human leukocyte antigen (HLA)-B27 transgenic rat model of spontaneous chronic inflammation. Experiments were performed using adult male HLAB27 rats, whereas healthy nontransgenic F344 rats served as controls. Enteric-coated rhIL-11 multi-particles (equivalent to 500 µg/kg rhIL11) or placebo (formulation lacking rhIL-11) were administrated orally on alternate days for 2 weeks to HLA-B27 or F344 rats. Stool character was observed daily during the treatment period. Animals were euthanized at the end of treatment and colonic inflammation was evaluated be measuring tissue myeloperoxidase (MPO) activity. Epithelial transport in isolated colonic mucosal sheets was studied in modified Ussing chambers. Oral treatment of HLA-B27 rats with rhIL-11 reduced MPO activity in the colon and suppressed the clinical signs of diarrhea. The electrophysiological characteristics of mucosal transport were improved in the HLA-B27 rats treated with rhIL-11 compared with placebo. After rhIL-11 treatment the basal transepithelial resistance and the estimated paracellular resistance were significantly increased, neurally mediated secretory responses to electrical field stimulation were improved, and cholinoceptor sensitivity was normalized. Treatment with rhIL-11 had no significant effect on basal short circuit current and the maximal secretory response to carbachol or substance P. Our data demonstrate that oral rhIL-11 therapy is associated with suppression of mucosal inflammation and a concomitant improvement of epithelial resistance and neurally mediated secretion in a model of chronic HLA-B27 colitis.

Address correspondence to: Dr. Beverley Greenwood-Van Meerveld, V.A. Medical Center, Research Administration Room 151, 921 NE 13th St., Oklahoma City, OK 73104. E-mail: beverley-greenwood{at}ouhsc.edu

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