Regulatory Peptides 97 (2001) 111–119 www.elsevier.com / locate / regpep Effect of recombinant human interleukin-11 on motilin and substance P release in normal and inflamed rabbits a a a b a Inge Depoortere , Theo Thijs , Leen Thielemans , James C. Keith Jr. , Gert Van Assche , a, * Theo L. Peeters a Centre for Gastroenterological Research, Department of Pathophysiology, University of Leuven, Gasthuisberg O&N, B-3000 Leuven, Belgium b Genetics Institute, Andover, MA, USA Received 4 May 2000; received in revised form 9 August 2000; accepted 9 August 2000 Abstract Recombinant human interleukin-11 (rhIL-11) normalizes depressed smooth muscle tension generation towards motilin and substance P (SP) in rabbits with colitis. The aim of this paper was to evaluate the effect of rhIL-11 treatment on motilin and SP release which could have an effect on the contractility changes. Rabbits received 4, 40, 72 or 720 mg / kg rhIL-11 s.c. or saline, 1 h later a continuous s.c. administration of rhIL-11 was started with or without the induction of colitis (135 mg / kg TNBS) for 5 days. Motilin and SP levels were measured by RIA, motilin mRNA expression by RT-PCR. TNBS-colitis did not affect plasma motilin levels but increased the motilin content of the duodenal mucosa 1.7-fold. rhIL-11 treatment dose-dependently increased plasma motilin levels (720 mg/kg day: 3.5-fold) and the motilin content of the duodenal mucosa (720 mg / kg day: 3.0-fold). The effects of rhIL-11 were similar in normal rabbits and were accompanied by an increased motilin mRNA expression. TNBS-colitis decreased plasma SP levels 2.7-fold and the SP content in the colonic muscle layer 7.1-fold. The decrease in the muscle layer, but not in the plasma, was normalized by rhIL-11 treatment. In normal rabbits, rhIL-11 caused a decrease in plasma SP levels, but had no effect on the tissue content of SP. In conclusion, treatment of inflamed or normal rabbits with rhIL-11 increases plasma and tissue levels of motilin in the duodenal mucosa via an increased expression of motilin in the endocrine cells and induces the release of SP from extrinsic neurons. These changes do not explain the beneficial effect of rhIL-11 on the lowered contractility in inflamed rabbits although a change in balance of neuropeptides may influence gastro-intestinal inflammation.  2001 Elsevier Science B.V. All rights reserved. Keywords: Colitis; Neuropeptides; Interleukin; Expression; Hormone level 1. Introduction of the protective effects of the cytokine against injury to the intestinal mucosa in Crohn’s disease (CD). It was IL-11 is a cytokine first identified in an immortalized reported recently that short-term treatment with rhIL-11 is primate bone marrow stromal cell line that stimulated the well tolerated and appears effective in inducing remission proliferation of an interleukin 6-dependent murine plas- in a subset of patients with active Crohn’s disease [3]. macytoma cell line [1]. In accordance with this finding, Inflammatory processes in the gastrointestinal tract not most studies of IL-11 have focused on its role in hemato- only affect the mucosa and submucosa, but also disturb the poiesis. However, IL-11 has been shown to have a variety contractile response of its neuromuscular layers. In this of other effects including the reduction of epithelial respect it is of interest to note that continuous subcuta- damage in models of intestinal injury (for a review see neous administration of rhIL-11 normalizes depressed Ref. [2]). These observations have prompted an evaluation tension generation in the colon in response towards receptor-mediated (motilin, ACh, substance P) and re- ceptor-independent (KCl) contractile agents in a rabbit *Corresponding author. Tel.: 1 32-16-345-757; fax: 1 32-16-345-939. E-mail address: theo.peeters@med.kuleuven.ac.be (T.L. Peeters). model of TNBS-induced colitis [4]. Therefore, the use of 0167-0115 / 01 / $ – see front matter  2001 Elsevier Science B.V. All rights reserved. PII: S0167-0115(00)00190-7