Abstract
Background and AimThe etiology of post-inflammatory gastrointestinal (GI) motility dysfunction, after resolution of acute symptoms of inflammatory bowel diseases (IBD) and intestinal infection, is largely unknown, however, a possible involvement of T cells is suggested.MethodsUsing the mouse model of T cell activation-induced enteritis, we investigated whether enhancement of smooth muscle cell (SMC) contraction by interleukin (IL)-17A is involved in postinflammatory GI hypermotility.ResultsActivation of CD3 induces temporal enteritis with GI hypomotility in the midst of, and hypermotility after resolution of, intestinal inflammation. Prolonged upregulation of IL-17A was prominent and IL-17A injection directly enhanced GI transit and contractility of intestinal strips. Postinflammatory hypermotility was not observed in IL-17A-deficient mice. Incubation of a muscle strip and SMCs with IL-17A in vitro resulted in enhanced contractility with increased phosphorylation of Ser19 in myosin light chain 2 (p-MLC), a surrogate marker as well as a critical mechanistic factor of SMC contractility. Using primary cultured murine and human intestinal SMCs, IκBζ- and p38 mitogen-activated protein kinase (p38MAPK)-mediated downregulation of the regulator of G protein signaling 4 (RGS4), which suppresses muscarinic signaling of contraction by promoting inactivation/desensitization of Gαq/11 protein, has been suggested to be involved in IL-17A-induced hypercontractility. The opposite effect of L-1β was mediated by IκBζ and c-jun N-terminal kinase (JNK) activation.ConclusionsWe propose and discuss the possible involvement of IL-17A and its downstream signaling cascade in SMCs in diarrheal hypermotility in various GI disorders.
Highlights
GI motility disorders, such as GI infection, inflammatory bowel diseases (IBD), ileus, achalasia and functional gastrointestinal disease, have been associated with immune activation [1,2,3,4,5]
small intestinal (SI) strips isolated on day 7 showed enhanced contractile responses upon stimulation by an acetylcholine (ACh) analog, carbamylcholine chloride (CCh) (Figures 1B)
The antibody induced only a modest elevation in the level of SI tumor necrosis factor a (TNF-a), IL-1b, IFN-c, IL-4 and IL-23 proteins while IL-6 and IL-17A increased by several fold
Summary
GI motility disorders, such as GI infection, IBD, ileus, achalasia and functional gastrointestinal disease, have been associated with immune activation [1,2,3,4,5]. Using a mouse model of T cell activation-induced enteritis, we show IL-17A may be involved in GI hypermotility in the model by inducing hypercontractility in SMCs. the model may not directly reflect the pathological situations of clinical IBD nor IBS, and IL-17A is not essential for induction of inflammation in this model, the present findings address the possibility that IL-17A may modulate GI motility in the healing stage after intestinal inflammation. The etiology of post-inflammatory gastrointestinal (GI) motility dysfunction, after resolution of acute symptoms of inflammatory bowel diseases (IBD) and intestinal infection, is largely unknown, a possible involvement of T cells is suggested
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