Cytokine-induced alterations of gastrointestinal motility in gastrointestinal disorders

Abstract

Inflammation and immune activation in the gut are usually accompanied by alteration of gastrointestinal (GI) motility. In infection, changes in motor function have been linked to host defense by enhancing the expulsion of the infectious agents. In this review, we describe the evidence for inflammation and immune activation in GI infection, inflammatory bowel disease, ileus, achalasia, eosinophilic esophagitis, microscopic colitis, celiac disease, pseudo-obstruction and functional GI disorders. We also describe the possible mechanisms by which inflammation and immune activation in the gut affect GI motility. GI motility disorder is a broad spectrum disturbance of GI physiology. Although several systems including central nerves, enteric nerves, interstitial cells of Cajal and smooth muscles contribute to a coordinated regulation of GI motility, smooth muscle probably plays the most important role. Thus, we focus on the relationship between activation of cytokines induced by adaptive immune response and alteration of GI smooth muscle contractility. Accumulated evidence has shown that Th1 and Th2 cytokines cause hypocontractility and hypercontractility of inflamed intestinal smooth muscle. Th1 cytokines downregulate CPI-17 and L-type Ca(2+) channels and upregulate regulators of G protein signaling 4, which contributes to hypocontractility of inflamed intestinal smooth muscle. Conversely, Th2 cytokines cause hypercontractilty via signal transducer and activator of transcription 6 or mitogen-activated protein kinase signaling pathways. Th1 and Th2 cytokines have opposing effects on intestinal smooth muscle contraction via 5-hydroxytryptamine signaling. Understanding the immunological basis of altered GI motor function could lead to new therapeutic strategies for GI functional and inflammatory disorders.

Keywords: Cytokine; Immunology; Inflammation; Motility.

Figure 1

Development of Th1, Th2, Th17 and induced Treg cells from naïve CD4+ T cells. Cytokines that inhibit the development of Th17 cells are marked in red. CD: Crohn’s disease; T-bet: T box expressed in T cells; GATA: GATA-binding protein; ROR: Retinoid-related orphan receptor; Foxp3: Forkhead box P3; STAT: Signal transducer and activator of transcription; IL: Interleukin; IFN: Interferon; TGF: Transforming growth factor.

Figure 2

Muscarinic receptor signaling pathways. Gastrointestinal smooth muscle expresses both M2 and M3 muscarinic receptors. The M3 receptors are coupled to Gq/11, which activates phospholipase C (PLC) and produce inositol 1,4,5-triphosphate (IP3) and diacylglycerol (DG). These second messengers elicit the activation of PKC and trigger an increase in [Ca²⁺]_i. M2 receptors are coupled to Gi/o, accompanied by adenylcyclase (AC), which causes a decrease in cAMP level and activation of phosphoinositol 3-kinase (PI3K) and integrin-linked kinase (ILK). Regulators of G protein signaling (RGS4) plays an important role in regulating smooth muscle contraction. To initiate contraction, increases in [Ca²⁺]_i activate MLCK, a Ca²⁺/calmodulin-dependent enzyme. MLCK phosphorylates LC20 on Ser-19, which results in contraction of smooth muscle through increases in myosin ATPase activity and cross-bridge cycling. MLCP is responsible for the dephosphorylation of LC20, which results in relaxation of smooth muscle. It is the balance between MLCK and MLCP activities that dictates the contractile activity of smooth muscle. Although MLCK is Ca²⁺/calmodulin dependent, MLCP functions independently of Ca²⁺/calmodulin and is regulated directly by phosphorylation of the myosin targeting subunit of MLCP and/or indirectly via phosphorylation of CPI-17. IL-1β upregulates RGS4 expression by inhibiting NF-κB activation. IL-1β also downregulates CPI-17 expression leading to muscle relaxation. PKC: Protein kinase C; MLCK: Myosin light chain kinase; MLCP: Myosin light chain phosphatase; NF-κB: Nuclear factor κB.