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-alpha suppressed their contractile response to ACh and the expression of the pore-forming alpha(1C) subunit of Ca(v)1.2 channels. VIP reversed both effects by blocking the translocation of NF-kappaB to the nucleus and its binding to the kappaB recognition sites on halpha(1C)1b promoter. The translocation of NF-kappaB was inhibited by blocking the degradation of IkappaBbeta. 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-kappaB. The infusion of exogenous VIP mitigates colonic inflammatory response and smooth muscle dysfunction.
Shi
Xuan-Zheng
XZ
Division of Gastroenterology, Department of Internal Medicine, Enteric Neuromuscular Disorders and Visceral Pain Center, The University of Texas Medical Branch at Galveston, Texas 77555-1064, USA.
Sarna
Sushil K
SK
D000109:Acetylcholine / Q000494:pharmacology; D021581:Active Transport, Cell Nucleus; D000818:Animals; D001665:Binding Sites; D020746:Calcium Channels, L-Type / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D003092:Colitis / Q000139:chemically induced / Q000276:immunology / Q000378:metabolism* / Q000503:physiopathology / Q000517:prevention & control; D003106:Colon / Q000187:drug effects / Q000276:immunology / Q000294:innervation* / Q000503:physiopathology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D017615:Enteric Nervous System / Q000187:drug effects / Q000276:immunology / Q000378:metabolism* / Q000503:physiopathology; D006706:Homeostasis; D006727:Hormone Antagonists / Q000494:pharmacology; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D066298:In Vitro Techniques; D018836:Inflammation Mediators / Q000378:metabolism*; D055104:Infusions, Subcutaneous; D009119:Muscle Contraction; D009130:Muscle, Smooth / Q000187:drug effects / Q000276:immunology / Q000294:innervation* / Q000503:physiopathology; D016328:NF-kappa B / Q000378:metabolism; D015213:Neuroimmunomodulation / Q000187:drug effects; D011401:Promoter Regions, Genetic; D051381:Rats; D017207:Rats, Sprague-Dawley; D051239:Receptors, Vasoactive Intestinal Peptide, Type II / Q000037:antagonists & inhibitors / Q000378:metabolism; D051238:Receptors, Vasoactive Intestinal Polypeptide, Type I / Q000037:antagonists & inhibitors / Q000378:metabolism; D013997:Time Factors; D014162:Transfection; D014302:Trinitrobenzenesulfonic Acid; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014660:Vasoactive Intestinal Peptide / Q000008:administration & dosage / Q000378:metabolism* / Q000494:pharmacology
C079146:CACNA1C protein, human; D020746:Calcium Channels, L-Type; D006727:Hormone Antagonists; C083487:I kappa B beta protein; D020672:I-kappa B Proteins; D018836:Inflammation Mediators; D016328:NF-kappa B; D051239:Receptors, Vasoactive Intestinal Peptide, Type II; D051238:Receptors, Vasoactive Intestinal Polypeptide, Type I; D014409:Tumor Necrosis Factor-alpha; C048507:vasoactive intestinal peptide, 4-chloro-Phe(6)-Leu(17)-; D014660:Vasoactive Intestinal Peptide; D014302:Trinitrobenzenesulfonic Acid; D000109:Acetylcholine