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

Abstract

Mediators such as prostaglandin E(2) (PGE(2)) and norepinephrine (NE) regulate macrophage (Mφ) responsiveness. Activation of alpha(2)-adrenergic receptors on Mφ potentiates lipopolysaccharide (LPS)-stimulated tumor necrosis factor (TNFalpha) production. PGE(2) inhibits LPS-stimulated TNFalpha production and gene expression, a response that can be desensitized by pretreatment of Mφ with PGE(2). We have determined that concomitant pretreatment of Mφ with PGE(2) and the alpha(2)-adrenergic agonist UK-14304 (UK) can prevent the PGE(2)-induced desensitization. PGE(2) concentration-effect curves have been determined for the inhibition of LPS-stimulated TNFalpha production by murine peritoneal Mφ. The addition of 10 nM UK to Mφ in culture significantly shifts the PGE(2) concentration-effect curve to the right; pretreatment of Mφ with UK significantly shifts the PGE(2) concentration-effect curve to the left; and pretreatment with the cyclooxygenase inhibitor, indomethacin, increases the maximum response of PGE(2). Preincubation of Mφ with PGE(2) (0.5 h) followed by washing significantly shifts the subsequent PGE(2) concentration-effect curve to the right. Concomitant preincubation of Mφ 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 UK increases LPS-induced TNFalpha mRNA accumulation, and this is blocked by yohimbine, while PGE(2) decreases TNFalpha mRNA accumulation. Preincubation of Mφ with PGE(2) prevents PGE(2) regulation of TNFalpha mRNA, and concomitant preincubation of Mφ with PGE(2) and UK reverses this effect. These investigations support the role of NE as a regulator of Mφ TNFalpha production, a response that has functional interactions with Mφ sensitivity to PGE(2).