Endogenous glucocorticoids modulate neutrophil migration and synovial P-selectin but not neutrophil phagocytic or...

Pharmacologic glucocorticoids are powerful inhibitors of the inflammatory response at many levels, including leucocyte trafficking and function. The adhesion molecule P-selectin is a key participant in polymorphonuclear neutrophil (PMN) migration to sites of inflammation. The extent to which endogenous glucocorticoids influence PMN migration and activation is not clear. We used the glucocorticoid receptor antagonist RU486 to examine the effect of endogenous glucocorticoid blockade on PMN migration and function in carrageenan monoarthritis in the rat. Arthritis was induced by intraarticular injection of carrageenan and disease severity measured by PMN count in synovial lavage fluid. Decalcified frozen sections of injected joints were analysed for expression of P-selectin by immunohistochemistry. Adrenal glucocorticoid action was blocked in vivo with RU486 20 mg/kg. PMN phagocytosis and reactive oxygen species synthesis were measured by flow cytometry. Carrageenan injection was associated with severe arthritis (synovial lavage PMN 5.9 +/- 0.7 x 10(6), P < 0.01 versus control) which was dose-dependent. P-selectin was not detected in normal joints but was abundant in joints injected with 500 microg carrageenan. RU486 resulted in exacerbation of carrageenan arthritis (9.7 +/- 0.8 x 10(6), P < 0.05). RU486 also altered the threshold for disease induction, in that most RU486-treated animals were susceptible to arthritis at a dose of carrageenan (2.5 microg) which did not induce arthritis in most control-treated animals (P < 0.05), denoting an altered threshold for arthritis induction. RU486 treatment was associated with increased synovial P-selectin expression. Activation status as measured by PMN phagocytic and oxidative function were not influenced by endogenous glucocorticoid blockade. These findings suggest that endogenous glucocorticoids selectively influence PMN migration to inflamed joints via P-selectin expression, but have no effect on PMN activation status.