Interactions between the alpha(2)-adrenergic and the prostaglandin response in the regulation of macrophage-derived tumor necrosis factor

Mediators such as prostaglandin E-2 (PGE(2)) and norepinephrine (NE) regula te macrophage (M phi) responsiveness. Activation of alpha(2)-adrenergic rec eptors on M phi potentiates lipopolysaccharide (LPS)-stimulated tumor necro sis factor (TNF alpha) production. PGE(2) inhibits LPS-stimulated TNF alpha production and gene expression, a response that can be desensitized by pre treatment of M phi with PGE(2). We have determined that concomitant pretrea tment of M phi with PGE(2) and the alpha(2)-adrenergic agonist UK-14304 (UK ) can prevent the PGE(2)-induced desensitization. PGE(2) concentration-effe ct curves have been determined for the inhibition of LPS-stimulated TNF alp ha production by murine peritoneal M phi. The addition of 10 nM UK to M phi in culture significantly shifts the PGE(2) concentration-effect curve to t he right; pretreatment of M phi with UK significantly shifts the PGE(2) con centration-effect curve to the left; and pretreatment with the cyclooxygena se inhibitor, indomethacin, increases the maximum response of PGE(2). Prein cubation of M phi with PGE(2) (0.5 h) followed by washing significantly shi fts the subsequent PGE(2) concentration-effect curve to the right. Concomit ant preincubation of M phi with PGE(2) and UK prevents this rightward shift , an effect that is blocked by the alpha(2)-adrenergic receptor antagonist yohimbine. Northern blot analysis demonstrates that UR increases LPS-induce d TNF alpha mRNA accumulation, and this is blocked by yohimbine, while PGE( 2) decreases TNF alpha mRNA accumulation. Preincubation of M phi with PGE(2 ) prevents PGE(2) regulation of TNF alpha mRNA, and concomitant preincubati on of M phi with PGE(2) and UK reverses this effect. These investigations s upport the role of NE as a regulator of M phi TNF alpha production, a respo nse that has functional interactions with M phi sensitivity to PGE(2). (C) 2000 Academic Press.