Tyrosine kinase regulatory action on ileal muscarinic effects of IFN-gamma.
Interferon-gamma (IFN-gamma) is a pleiotropic cytokine that has a large number of immunologic and nonimmunologic functions. We have described that IFN-gamma could activate muscarinic cholinergic receptors (mAchR) of rat intestine, stimulating ileal motility. We also observed that mAchR activation induced inhibition of cAMP levels and stimulation of cGMP formation. The objectives of our work were to clarify the signal transduction pathways involved in regulation of ileal motility through mAchR activation by IFN-gamma. Our results demonstrate that this cytokine produces an ileal cholinergic response through tyrosine kinase activity. The activation of tyrosine kinase mediates ileal contractility, phosphoinositide hydrolysis by phospholipase C, nitric oxide synthase via protein kinase C, and cGMP synthesis. The increment in ileal motility is probably due to hyperproduction of prostaglandin E2 (PGE2) by ileal tissue. This prostanoid is an important mediator because it stimulates ileal motility. We conclude that IFN-gamma not only immunomodulates the gut microenvironment but also exerts a local nonimmunologic regulation on intestinal motility.
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CEFYBO, Consejo Nacional de Investigaciones Cientificas y Técnicas, Buenos Aires, Argentina. mesales@mail.retina.ar
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D000818:Animals; D006152:Cyclic GMP / Q000378:metabolism; D004789:Enzyme Activation; D005769:Gastrointestinal Motility / Q000187:drug effects; D006868:Hydrolysis; D007082:Ileum / Q000187:drug effects* / Q000201:enzymology; D007295:Inositol Phosphates / Q000378:metabolism; D007371:Interferon-gamma / Q000494:pharmacology*; D008297:Male; D018721:Muscarinic Agonists / Q000494:pharmacology*; D019001:Nitric Oxide Synthase / Q000187:drug effects; D011493:Protein Kinase C / Q000187:drug effects; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects; D013268:Stimulation, Chemical
D007295:Inositol Phosphates; D018721:Muscarinic Agonists; D007371:Interferon-gamma; D019001:Nitric Oxide Synthase; D011505:Protein-Tyrosine Kinases; D011493:Protein Kinase C; D006152:Cyclic GMP