Abstract
AimsInflammatory infiltrates and pro-inflammatory mediators are found increased in obstructive and functional bowel disorders, in which lumen distention is present. However, what caused the low level inflammation is not well known. We tested the hypothesis that lumen distention- associated mechanical stress may induce expression of specific inflammatory mediators in gut smooth muscle.MethodsStatic mechanical stretch (18% elongation) was applied in vitro in primary culture of rat colonic circular smooth muscle cells (RCCSMCs) with a Flexercell FX-4000 Tension Plus System. Mechanical distention in vivo was induced in rats with an obstruction band placed in the distal colon.ResultsIn the primary culture of RCCSMCs, we found that static stretch significantly induced mRNA expression of iNOS, IL-6, and MCP-1 in 3 hours by 6.0(±1.4), 2.5(±0.5), and 2.2(±0.5) fold (n = 6∼8, p<0.05), respectively. However, gene expression of TNF-α, IL-1β, and IL-8 was not significantly affected by mechanical stretch. In the in vivo model of colon obstruction, we found that gene expression of iNOS, IL-6, and MCP-1 is also significantly increased in a time-dependent manner in the mechanically distended proximal segment, but not in the sham controls or distal segments. The conditioned medium from the muscle strips of the stretched proximal segment, but not the distal segment or control, significantly induced translocation and phosphorylation of NF-κB p65. This treatment further increased mRNA expression of inflammatory mediators in the naïve cells. However, treatment of the conditioned medium from the proximal segment with neutralizing antibody against rat IL-6 significantly attenuated the activation of NF-κB and gene expression of inflammatory mediators.ConclusionsOur studies demonstrate that mechanical stress induces gene expression of inflammatory mediators i.e. iNOS, IL-6, and MCP-1 in colonic SMC. Further ex vivo study showed that mechanical stress functions as a pro-inflammatory stimulus in the gut.
Highlights
Inflammatory response in the gastrointestinal (GI) tract involves intricate coordination of numerous cellular and molecular events that are dictated by cytokines, chemokines, and other inflammatory mediators i.e. prostaglandins, nitric oxide and cell surface adhesion molecules [1,2]
We investigated whether mechanical stress induces gene expression of cytokines (i.e. TNF-a, IL-1b, and IL-6), chemokines (i.e. MCP-1 and IL-8), and other pro-inflammatory mediators in gut smooth muscle cells (SMCs) in the in vivo model of bowel obstruction and in vitro model of direct stretch in cultured colonic SMCs
We first determined if direct mechanical stretch induced gene expression of cytokines, chemokines and proinflammatory mediators in vitro in the primary culture of rat colonic circular smooth muscle cells (RCCSMCs)
Summary
Inflammatory response in the gastrointestinal (GI) tract involves intricate coordination of numerous cellular and molecular events that are dictated by cytokines, chemokines, and other inflammatory mediators i.e. prostaglandins, nitric oxide and cell surface adhesion molecules [1,2]. Prostaglandins and nitric oxide are well known mediators of gut motility function [8,9]. Recent studies show that gut motility function is markedly affected by cytokines such as IL-1b, TNF-a, IL-6, and intercellular adhesion molecule-1 [1,2,6,10]. Inflammatory mediators such as prostaglandins and cytokines contribute to visceral hyperalgesia and abdominal pain [11,12]. IL-6 is found to act on gut SMCs and sensory neurons, and affect both motility function and visceral sensitivity [10,12,13,14]
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