motilin and Colitis

The underlying mechanisms of gastric dysfunction during or after an episode of intestinal inflammation are poorly understood. This study investigated the effects of colitis on the contractile effects of motilin, an important endocrine regulator of gastric motility, in the antrum.. Myeloperoxidase (MPO) activity, NF-kappaB activity and motilin receptor density were determined in the antrum of rabbits 5 days after the induction of 2,4,6-trinitrobenzenesulphonic acid colitis. Smooth muscle and neural responses to motilin were studied in antral smooth muscle strips in vitro.. Colitis did not affect MPO activity, but increased NF-kappaB activity in the antrum. Motilin receptor density in the antrum was not affected. Under control conditions, motilin induced a slowly developing tonic smooth muscle contraction. Five days post-inflammation, tonic contractions to motilin were reduced and preceded by a rapid initial contraction. Other kinases were recruited for the phosphorylation of myosin light chain (MLC) (a multi-functional MLC kinase), and for the inhibition of MLC phosphatase (Rho kinase in addition to protein kinase C) to mediate the motilin-induced contractions during inflammation. Colitis potentiated the cholinergic neural on-contractions in the antrum. This was associated with a hyper-reactivity to motilin and an increased muscle response to ACh.. Colitis altered the course of the motilin-induced smooth muscle contraction in the antrum. This involved changes in the kinases phosphorylating MLC. Increased cholinergic excitability to motilin in the antrum may play a role in the pathogenesis of inflammation-associated gastric motility disorders.

Topics: Animals; Colitis; Enzyme Activation; Female; Male; Motilin; Muscle Contraction; Muscle, Smooth; Myosin Light Chains; Myosin-Light-Chain Kinase; Myosin-Light-Chain Phosphatase; NF-kappa B; Peroxidase; Phosphorylation; Protein Kinase C; Pyloric Antrum; Rabbits; Receptors, Gastrointestinal Hormone; Receptors, Neuropeptide; rho-Associated Kinases; Signal Transduction; Trinitrobenzenesulfonic Acid

Treatment with the anti-inflammatory cytokine, interleukin-11 (IL-11), in rabbits with TNBS-colitis reduces tissue damage but does not normalize body weight loss despite an increase in plasma levels of motilin, known to stimulate food intake. We investigated whether IL-11 could increase plasma levels of the anorectic peptide, leptin in non-inflamed and inflamed rabbits. In addition, the effect of IL-11 and leptin on motilin mRNA expression in the T84 cell line was tested. Five days post-inflammation, weight loss amounted 10.7+/-1.2%, but plasma leptin and motilin levels were unaffected. During IL-11 treatment, weight loss remained and plasma leptin levels dose-dependently increased with 27+/-5% (4 microg/kg day) and 108+/-7% (720 microg/kg day). Motilin levels increased in parallel with 23+/-12% or 256+/-97%. In non-inflamed animals, a prompt decrease in weight (-11.9+/-1%) was observed after treatment with the highest dose of IL-11 and this was associated with an increase in plasma leptin (70+/-18%) and motilin levels (113+/-7%). Both IL-11 and leptin stimulated motilin mRNA expression in T84 cells with a different time profile. In conclusion, the increase in plasma leptin levels during IL-11 treatment induces wasting in normal rabbits and may be one of the major factors involved in the maintenance of body weight loss in rabbits with colitis. Increase of motilin expression by leptin may be part of a feedback mechanism.

Topics: Animals; Cell Line; Colitis; Gene Expression Regulation; Inflammation; Interleukin-11; Leptin; Motilin; Rabbits; RNA, Messenger; Weight Loss

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 microg/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 microg/kg day: 3.5-fold) and the motilin content of the duodenal mucosa (720 microg/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.

Topics: Animals; Base Sequence; Colitis; DNA Primers; Female; Humans; Interleukin-11; Intestinal Mucosa; Male; Motilin; Rabbits; Recombinant Proteins; RNA, Messenger; Substance P

We studied the effect of recombinant human interleukin-11 (rhIL-11), a cytokine with protective effects against injury to the intestinal mucosa, on inflammatory changes in the muscle layers of the gut, in rabbits with colitis. A single dose of rhIL-11 (4, 40, or 720 microg/kg) was given 1 h before colitis was induced with 135 mg/kg 2, 4,6-trinitrobenzene sulfonic acid (TNBS), followed by a continuous s. c. administration of 4, 40, or 720 microg/kg. day rhIL-11 or saline for 5 days. Colitis affected mucosal architecture, general mechanical properties (passive tension increased with 12.3 g/mm(2), optimal stretch decreased with 26%), and collagen content (decreased from 366 +/- 25 to 237 +/- 13 microg/mg of protein). Changes in passive tension and collagen content were normalized by the highest and lowest dose of rhIL-11, respectively, but neither dose could normalize the optimal stretch. Colitis also decreased maximal contractile tension in response to acetylcholine (ACh), motilin, substance P (SP), K(+), and prostaglandin E(2) but this was normalized with 40 microg/kg. day (motilin, SP) and 720 microg/kg. day (ACh, K(+)) rhIL-11 but not for prostaglandin E(2). For motilin and SP, receptor density was decreased in colitis and normalized in treated rabbits. Colitis also increased the contractile potency toward ACh, an effect already reversed by rhIL-11, 4 microg/kg. day. In conclusion, rhIL-11 partially normalizes disturbed tension generation in experimental colitis. The use of this cytokine in the treatment of irritable bowel disease may contribute to the restoration of motor dysfunction.

Topics: Acetylcholine; Animals; Colitis; Colon; Dinoprostone; Dose-Response Relationship, Drug; Female; In Vitro Techniques; Interleukin-11; Male; Motilin; Muscle Contraction; Muscle, Smooth; Potassium Chloride; Rabbits; Receptors, Gastrointestinal Hormone; Receptors, Neurokinin-1; Receptors, Neuropeptide; Recombinant Proteins; Reverse Transcriptase Polymerase Chain Reaction; Substance P; Tensile Strength; Trinitrobenzenesulfonic Acid

To test the hypothesis that the changes in intestinal contractility, which accompany inflammation of the gut, are agonist specific, we compared the response of inflamed strips to substance P (SP), motilin, ACh, and K(+) as a function of time. In parallel experiments, changes in the general mechanical properties (passive tension, optimal stretch) of the colitic tissue were evaluated. Colitis was induced by trinitrobenzenesulfonic acid, and rabbits were killed after 1, 2, 3, 5, or 8 days. Passive tension was increased starting from day 2 until day 8, and maximal active tension (T(max)) was generated at less stretch from day 5. A 50% decrease in T(max) was observed for ACh and K(+) between days 2 and 3 and for motilin and SP between days 3 and 5. For all compounds, T(max) returned to normal after 8 days. The pEC(50) value (negative logarithm of the concentration that induces 50% of the maximal contractile activity) for ACh was increased from day 3 until day 8 and for SP at day 3, whereas for motilin it was decreased at day 1. The changes in passive tension and optimal stretch indicate generalized structural alterations of smooth muscle tissue. However, the different time profiles of the changes in active tension and contractile potency for different contractile agents suggest that inflammation specifically affects receptor-mediated mechanisms.

Topics: Acetylcholine; Animals; Colitis; Colon; Female; Gastrointestinal Motility; In Vitro Techniques; Male; Motilin; Potassium; Rabbits; Substance P