BETA-ADRENERGIC-RECEPTOR REGULATION OF MACROPHAGE-DERIVED TUMOR-NECROSIS-FACTOR-ALPHA PRODUCTION FROM RATS WITH EXPERIMENTAL ARTHRITIS

Prostaglandin E(2) (PGE(2)) and beta-adrenergic agonists can suppress lipopolysaccharide-induced tumor necrosis factor-alpha (TNF) productio n from elicited macrophages. We assessed the responsiveness of rat per itoneal macrophages to PGE(2) and the beta-adrenergic agonist isoprote renol during immunologically-mediated arthritis. We assessed macrophag e sensitivity to these mediators from resident macrophages and macroph ages elicited with either streptococcal cell wall or complete Freund's adjuvant. Peritoneal macrophages were obtained from female Lewis rats that were (1) injected with complete Freund's adjuvant and non-arthri tic (CFA); (2) injected with streptococcal cell wall and arthritic (AR T); (3) injected with streptococcal cell wall and non-reactive (NON) a nd (3) non-elicited resident macrophages (RES). When challenged with g raded concentrations of lipopolysaccharide (0.1 to 10,000 ng/ml), macr ophages obtained from each group of rats released TNF in a concentrati on-dependent manner, with macrophages from arthritic rats (ART) produc ing the greatest amount of TNF (p < 0.001). While PGE(2) suppressed li popolysaccharide (100 ng/ml) stimulated TNF production in a concentrat ion-dependent manner in all groups. the greatest sensitivity to PGE(2) was observed with macrophages obtained from rats which received strep tococcal cell wall when compared to both complete Freund's adjuvant-el icited and resident macrophages (p < 0.05). The beta-adrenergic agonis t isoproterenol also inhibited lipopolysaccharide-stimulated TNF produ ction from macrophages in all groups. In addition, the specific beta(2 )-adrenergic antagonist, ICI 118.551, shifted isoproterenol concentrat ion-effect curves to the right (p < 0.01). Minimal responsiveness to i soproterenol was observed with resident peritoneal macrophages. Maximu m isoproterenol-induced inhibition of TNF production was observed with complete Freund's adjuvant-elicited macrophages, and significantly le ss in macrophages of streptococcal cell wall-injected rats. Of particu lar interest, macrophages obtained from streptococcal cell wall-inject ed rats, which became arthritic, were significantly less sensitive to isoproterenol than those which did not develop arthritis (p < 0.02). I n addition, these changes in sensitivity were not reflected by changes in the sensitivity of both CFA and ART groups to dibutyryl cAMP. The present study demonstrates a shift in the balance between inhibitory m ediator responses in rats inoculated with one of two different adjuvan ts. These investigations support the role of PGE(2) and a neurotransmi tter as immunomodulating compounds which may effectively maintain an i nflammatory lesion such as arthritis.