title: Regulation of macrophage-derived tumor necrosis factor production by modification of adrenergic receptor sensitivity.
abstract: Catecholamines and prostaglandins are among the many diverse mediators which participate in an interactive communication between the nervous and immune systems. We have examined the response of murine peritoneal macrophages (M luminal diameter) to prostaglandin-E2 (PGE2) and the beta-adrenergic agonist isoproterenol. In the present study we found a relationship between the response elicited by PGE2 and a beta-adrenergic agonist, which in a fashion similar to the response of PGE2 on M luminal diameters suppresses lipopolysaccharide (LPS)-induced tumor necrosis factor (TNF) production. It has been established that exposure of M luminal diameters to PGE2 desensitizes the suppressive function of PGE2. In this study, prior exposure of M luminal diameters to a beta-adrenergic agonist and the effects on subsequent beta-adrenergic responses, as well as the relationship to PGE2 sensitivity was determined. Complete Freund's adjuvant-elicited M luminal diameters were incubated with or without either a beta-adrenergic agonist or antagonist. All groups of cells were then extensively washed, followed by incubation with LPS (100 ng/ml) with or without graded concentrations of PGE2 or the beta-adrenergic agonist isoproterenol. Supernatants were collected to determine TNF concentrations by a fibroblast cytolytic assay, and Northern blot analysis was used to determine changes in the regulation of TNF mRNA accumulation. Both isoproterenol and PGE2 inhibited LPS-stimulated TNF release and TNF mRNA accumulation. We have established M luminal diameters regulation of sensitivity to isoproterenol-induced suppression of TNF production. The isoproterenol concentration-effect curve was shifted to the right after pre-exposure of M luminal diameter to the beta-agonist, suggesting a desensitized beta-adrenergic receptor population. Further studies demonstrated that M luminal diameters pre-exposed to the beta-adrenergic antagonist, ICI 118.551, washed, and then challenged with LPS show an increased sensitivity for isoproterenol-induced suppression of TNF production. In addition, a decreased sensitivity of M luminal diameters to exogenous PGE2 was observed during the desensitization to the beta-adrenergic agonist. Although concomitant addition of isoproterenol increased PGE2-induced suppression of LPS-stimulated TNF production, M luminal diameter pre-exposed to isoproterenol (10(-6) M) demonstrated a decreased sensitivity for PGE2-induced suppression of LPS-stimulated TNF production and TNF mRNA accumulation. Our results show that the effects observed after acute administration of a mediator may be different when M luminal diameters have been previously exposed to that or other mediators. These investigations support a role for mediators released from the nervous system to regulate the release of a cytokine needed to maintain inflammatory responses.
authors.affiliation: Department of Pathology, SUNY at Buffalo, School of Medicine and Biomedical Sciences 14214, USA.
authors.forename: T A
authors.initials: TA
authors.lastname: Ignatowski
authors.forename: R N
authors.initials: RN
authors.lastname: Spengler
mesh_terms: D000276:Adjuvants, Immunologic / Q000494:pharmacology; D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000818:Animals; D002478:Cells, Cultured; D017931:DNA Primers / Q000737:chemistry; D015232:Dinoprostone / Q000494:pharmacology*; D005260:Female; D015870:Gene Expression; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D017737:Macrophages, Peritoneal / Q000378:metabolism*; D051379:Mice; D008808:Mice, Inbred CBA; D008969:Molecular Sequence Data; D011412:Propanolamines / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D000276:Adjuvants, Immunologic; D000318:Adrenergic beta-Agonists; D017931:DNA Primers; D008070:Lipopolysaccharides; D011412:Propanolamines; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; C026777:ICI 118551; D015232:Dinoprostone; D007545:Isoproterenol