The glucocorticoid-induced antiinflammatory protein lipocortin I is pr
esent in arthritic synovium but its ability to regulate joint inflamma
tion has not previously been studied. We investigated the role of lipo
cortin 1 in the antiinflammatory activity of glucocorticoids in an acu
te arthritis model induced by intraarticular injection of carrageenan.
Compared to control joints (0.09 +/- 0.08 x 10(6) synovial fluid cell
count), carrageenan injected joints exhibited marked infiltration of
PMN (10.2 +/- 0.7 x 10(6), p < 0.001). Both intraperitoneal (1.0 mg/kg
) and intraarticular administration (5 mu g) of dexamethasone (DEX) si
gnificantly suppressed arthritis severity (p < 0.001 and 0.005, respec
tively), and the effects of DEX were significantly prevented by intra-
articular injection of antilipocortin 1 mAb (p < 0.05). Carrageenan ar
thritis was also significantly inhibited by intraarticular administrat
ion of the N-terminal lipocortin 1 peptide Ac2-26 at doses of 1 or 2 m
g/kg (p < 0.01). Intraarticular injection antilipocortin 1 mAb in the
absence of DEX also significantly exacerbated arthritis severity (p <
0.005). In vitro treatment of PMN with DEX was associated with signifi
cant inhibition of phagocytosis (p < 0.005) and reactive oxygen specie
s (ROS) generation (p < 0.001). Antilipocortin 1 mAb significantly red
uced the inhibitory effects of DEX (p < 0.01 and 0.005, respectively).
These results demonstrate that lipocortin 1 mediates the effects of e
xogenous glucocorticoids on neutrophil migration in carrageenan-induce
d acute arthritis, exerts an endogenous antiinflammatory influence, an
d mediates glucocorticoid inhibition of neutrophil activation.