title: 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 (M&phi;) responsiveness. Activation of alpha(2)-adrenergic receptors on M&phi; 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 M&phi; with PGE(2). We have determined that concomitant pretreatment 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-effect curves have been determined for the inhibition of LPS-stimulated TNFalpha 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 the right; pretreatment of M&phi; 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 M&phi; with PGE(2) (0.5 h) followed by washing significantly shifts the subsequent PGE(2) concentration-effect curve to the right. Concomitant 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 UK increases LPS-induced TNFalpha mRNA accumulation, and this is blocked by yohimbine, while PGE(2) decreases TNFalpha mRNA accumulation. Preincubation of M&phi; with PGE(2) prevents PGE(2) regulation of TNFalpha mRNA, and concomitant preincubation of M&phi; with PGE(2) and UK reverses this effect. These investigations support the role of NE as a regulator of M&phi; TNFalpha production, a response that has functional interactions with M&phi; sensitivity to PGE(2).
authors.affiliation: Department of Pathology, SUNY at Buffalo, Buffalo, New York 14214, USA.
authors.forename: T A
authors.initials: TA
authors.lastname: Ignatowski
authors.forename: S L
authors.initials: SL
authors.lastname: Kunkel
authors.forename: R N
authors.initials: RN
authors.lastname: Spengler
mesh_terms: D000316:Adrenergic alpha-Agonists / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D000068438:Brimonidine Tartrate; D002478:Cells, Cultured; D015232:Dinoprostone / Q000378:metabolism* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005260:Female; D008070:Lipopolysaccharides / Q000494:pharmacology; D017737:Macrophages, Peritoneal / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D008808:Mice, Inbred CBA; D011810:Quinoxalines / Q000378:metabolism / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism*; D018341:Receptors, Adrenergic, alpha-2 / Q000378:metabolism* / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000235:genetics*
chemical_list: D000316:Adrenergic alpha-Agonists; D008070:Lipopolysaccharides; D011810:Quinoxalines; D012333:RNA, Messenger; D018341:Receptors, Adrenergic, alpha-2; D014409:Tumor Necrosis Factor-alpha; D000068438:Brimonidine Tartrate; D015232:Dinoprostone