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Cytokine modulation of muscarinic receptors in the murine intestine

¹Intestinal Disease Research Program, Department of Medicine, McMaster University, Hamilton, Ontario, Canada; ²and Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan

Submitted 26 November 2006 ; accepted in final form 5 April 2007

The extent to which gut motility and smooth muscle contractility are altered by intestinal inflammation depends on the nature of the underlying immune activation. The muscarinic receptor on smooth muscle plays a critical role in mediating acetylcholine-driven motor function. We examined the ability of cytokines to influence muscarinic receptor characteristics on intestinal longitudinal muscle and related the findings to studies on carbachol-induced contraction. Cells were isolated from longitudinal muscle myenteric plexus (LMMP). Cytokine receptor expression, muscle contractility, and muscarinic agonist receptor characteristics were examined by agonist displacement of [N-methyl-³H]scopolamine ([³H]NMS) binding. The TGF-1 receptor (543 bp) and the IFN- receptor 1 (660 bp) were identified on smooth muscle cells. Scatchard analysis revealed dissociation constant and maximum binding values for [³H]NMS of 2.6 nM and 2.4 x 10⁴ sites/cell, respectively, in control cells. Nematode infection was accompanied by a reduction in inhibitory constant of the high-affinity sites (K_H), and this was independent of signal transduction and activator of transcription 6. Preincubation with TGF-1 enhanced longitudinal muscle contractility and decreased the K_H to 2.2 pM (increased muscarinic receptor affinity), whereas preincubation with IFN- increased the K_H to 0.4 µM (decreased muscarinic receptor affinity) and decreased longitudinal muscle contractility. Preincubation of LMMP with IL-13 decreased the K_H to 0.2 nM. Cytokines exert differential effects on the muscarinic receptor on intestinal longitudinal smooth muscle. These findings explain the basis for altered muscle contractility observed in Th1 and Th2 models of inflammation, as well as in the post-nematode-infected state.

interleukin-13; transforming growth factor-; intestinal motility

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