Tyrosine kinase regulatory action on ileal muscarinic effects of IFN-gamma

Interferon-gamma (IFN-gamma) is a pleiotropic cytokine that has a large num ber of immunologic and nonimmunologic functions. We have described that IFN -gamma could activate muscarinic cholinergic receptors (mAchR) of rat intes tine, stimulating ileal motility. We also observed that mAchR activation in duced inhibition of cAMP levels and stimulation of cGMP formation. The obje ctives of our work were to clarify the signal transduction pathways involve d in regulation of ileal motility through mAchR activation by IFN-gamma. Ou r results demonstrate that this cytokine produces an ileal cholinergic resp onse through tyrosine kinase activity. The activation of tyrosine kinase me diates heal contractility, phophoinositide hydrolysis by phospholipase C, n itric oxide synthase via protein kinase C, and cGMP synthesis. The incremen t in ileal motility is probably due to hyperproduction of prostaglandin E-2 (PGE(2)) by ileal tissue. This prostanoid is an important mediator because it stimulates ileal motility. We conclude that IFN-gamma not only immunomo dulates the gut microenvironment but also exerts a local nonimmunologic reg ulation on intestinal motility.