Rc. Chou et al., BETA-ADRENERGIC-RECEPTOR REGULATION OF MACROPHAGE-DERIVED TUMOR-NECROSIS-FACTOR-ALPHA PRODUCTION FROM RATS WITH EXPERIMENTAL ARTHRITIS, Journal of neuroimmunology, 67(1), 1996, pp. 7-16
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.