Beta-adrenergic receptor regulation of macrophage-derived tumor necrosis factor-alpha production from rats with experimental arthritis.
Prostaglandin E2 (PGE2) and beta-adrenergic agonists can suppress lipopolysaccharide-induced tumor necrosis factor-alpha (TNF) production from elicited macrophages. We assessed the responsiveness of rat peritoneal macrophages to PGE2 and the beta-adrenergic agonist isoproterenol during immunologically-mediated arthritis. We assessed macrophage sensitivity to these mediators from resident macrophages and macrophages 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-arthritic (CFA); (2) injected with streptococcal cell wall and arthritic (ART); (3) injected with streptococcal cell wall and non-reactive (NON) and (4) non-elicited resident macrophages (RES). When challenged with graded concentrations of lipopolysaccharide (0.1 to 10,000 ng/ml), macrophages obtained from each group of rats released TNF in a concentration-dependent manner, with macrophages from arthritic rats (ART) producing the greatest amount of TNF (p < 0.001). While PGE2 suppressed lipopolysaccharide (100 ng/ml) stimulated TNF production in a concentration-dependent manner in all groups, the greatest sensitivity to PGE2 was observed with macrophages obtained from rats which received streptococcal cell wall when compared to both complete Freund's adjuvant-elicited and resident macrophages (p < 0.05). The beta-adrenergic agonist isoproterenol also inhibited lipopolysaccharide-stimulated TNF production from macrophages in all groups. In addition, the specific beta 2-adrenergic antagonist, ICI 118.551, shifted isoproterenol concentration-effect curves to the right (p < 0.01). Minimal responsiveness to isoproterenol was observed with resident peritoneal macrophages. Maximum isoproterenol-induced inhibition of TNF production was observed with complete Freund's adjuvant-elicited macrophages, and significantly less in macrophages of streptococcal cell wall-injected rats. Of particular interest, macrophages obtained from streptococcal cell wall-injected rats, which became arthritic, were significantly less sensitive to isoproterenol than those which did not develop arthritis (p < 0.02). In 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 mediator responses in rats inoculated with one of two different adjuvants. These investigations support the role of PGE2 and a neurotransmitter as immunomodulating compounds which may effectively maintain an inflammatory lesion such as arthritis.
Chou
R C
RC
Department of Pathology, School of Medicine and Biomedical Sciences, SUNY at Buffalo, NY 14214, USA.
Stinson
M W
MW
Noble
B K
BK
Spengler
R N
RN
D000818:Animals; D001169:Arthritis, Experimental / Q000276:immunology / Q000378:metabolism*; D001426:Bacterial Proteins / Q000276:immunology; D003994:Bucladesine / Q000494:pharmacology; D002462:Cell Membrane / Q000737:chemistry / Q000276:immunology; D004305:Dose-Response Relationship, Drug; D005069:Evaluation Studies as Topic; D005260:Female; D005620:Freund's Adjuvant; D007150:Immunohistochemistry; D007545:Isoproterenol / Q000276:immunology / Q000494:pharmacology; D008070:Lipopolysaccharides; D017737:Macrophages, Peritoneal / Q000737:chemistry / Q000276:immunology / Q000378:metabolism*; D051381:Rats; D011917:Rats, Inbred Lew; D011943:Receptors, Adrenergic, beta / Q000276:immunology*; D018078:Receptors, Prostaglandin E / Q000276:immunology / Q000502:physiology; D012680:Sensitivity and Specificity; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D013291:Streptococcus / Q000737:chemistry / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis* / Q000187:drug effects / Q000276:immunology
D001426:Bacterial Proteins; D008070:Lipopolysaccharides; D011943:Receptors, Adrenergic, beta; D018078:Receptors, Prostaglandin E; D014409:Tumor Necrosis Factor-alpha; D003994:Bucladesine; D005620:Freund's Adjuvant; D007545:Isoproterenol