Homeostatic and therapeutic roles of VIP in smooth muscle function: Myo-neuroimmune interactions

We tested the hypothesis that spontaneous release of vasoactive intestinal peptide (VIP) from enteric neurons maintains homeostasis in smooth muscle function in mild inflammatory insults and that infusion of exogenous VIP has therapeutic effects on colonic smooth muscle dysfunction in inflammation. In vitro experiments were performed on human colonic circular smooth muscle tissues and in vivo on rats. The incubation of human colonic circular smooth muscle strips with TNF-α suppressed their contractile response to ACh and the expression of the pore-forming α_1C subunit of Ca_v1.2 channels. VIP reversed both effects by blocking the translocation of NF-κB to the nucleus and its binding to the κB recognition sites on hα_1C1b promoter. The translocation of NF-κB was inhibited by blocking the degradation of IκBβ. Induction of inflammation by a subthreshold dose of 17 mg/kg trinitrobenzene sulfonic acid (TNBS) in rats moderately decreased muscularis externa concentration of VIP, and it had little effect on the contractile response of circular smooth muscle strips to ACh. The blockade of VIP and pituitary adenylate cyclase-activating peptide receptors 1/2 during mild inflammatory insult significantly worsened the suppression of contractility and the inflammatory response. The induction of more severe inflammation by 68 mg/kg TNBS induced marked suppression of colonic circular muscle contractility and decrease in serum VIP. Exogenous infusion of VIP by an osmotic pump reversed these effects. We conclude that the spontaneous release of VIP from the enteric motor neurons maintains homeostasis in smooth muscle function in mild inflammation by blocking the activation of NF-κB. The infusion of exogenous VIP mitigates colonic inflammatory response and smooth muscle dysfunction.