REGULATION OF MACROPHAGE-DERIVED TUMOR-NECROSIS-FACTOR PRODUCTION BY MODIFICATION OF ADRENERGIC-RECEPTOR SENSITIVITY

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 phi) to prostaglandin-E(2) (PGE(2)) and the beta-adrenergic agonist isoproterenol. In the present study we found a relationship between the response elicited by PGE(2) and a beta-adrenergic agonist, which in a fashion similar to the response of PGE(2) on M phi s suppresses lipopolysaccharide (LPS)-induced tumor necrosis factor (TNF) production. It has been established that exposure of M phi s to PGE(2) desensitizes the suppressive function of PGE(2). In this study, prior exposure of M phi s to a beta-adrenergic agonist and the effects on subsequent beta-adrenergic responses, as well as the relationship to PGE(2) sensitivity was determined. Complete Freund's adjuvant-elicited M phi s 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 PGE(2) 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 PGE(2) inhibited LPS-stimulated TNF release and TNF mRNA accumulation. We have established M phi s 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 phi to the beta-agonist, suggesting a desensitized beta-adrenergic receptor population. Further studies demonstrated that M phi s 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 phi s to exogenous PGE(2) was observed during the desensitization to the beta-adrenergic agonist. Although concomitant addition of isoproterenol increased PGE(2)-induced suppression of LPS - stimulated TNF production, M phi s pre-exposed to isoproterenol (10(-6) M) demonstrated a decreased sensitivity for PGE(2)-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 phi s 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.