ENDOGENOUS GLUCOCORTICOIDS MODULATE NEUTROPHIL MIGRATION AND SYNOVIALP-SELECTIN BUT NOT NEUTROPHIL PHAGOCYTIC OR OXIDATIVE FUNCTION IN EXPERIMENTAL ARTHRITIS

Pharmacologic glucocorticoids are powerful inhibitors of the inflammat ory response at many levels, including leucocyte trafficking and funct ion. The adhesion molecule P-selectin is a key participant in polymorp honuclear neutrophil (PMN) migration to sites of inflammation. The ext ent to which endogenous glucocorticoids influence PMN migration and ac tivation is not clear. We used the glucocorticoid receptor antagonist RU486 to examine the effect of endogenous glucocorticoid blockade on P MN migration and function in carrageenan monoarthritis in the rat. Art hritis was induced by intraarticular injection of carrageenan and dise ase severity measured by PMN count in synovial lavage fluid. Decalcifi ed 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 oxy gen species synthesis were measured by flow cytometry. Carrageenan inj ection was associated with severe arthritis (synovial lavage PMN 5.9 /- 0.7 x 10(6) P<0.01 ver-sus control) which was dose-dependent. P-sel ectin was not detected in normal joints but was abundant in joints inj ected with 500 mu g carrageenan. RU486 resulted in exacerbation of car rageenan arthritis (9.7 +/- 0.8x10(6), P<0.05). RU486 also altered the threshold for disease induction, in that most RU486-treated animals w ere susceptible to arthritis at a dose of carrageenan (2.5 mu g) which did not induce arthritis in most control-treated animals (P<0.05), de noting an altered threshold for arthritis induction. RU486 treatment w as associated with increased synovial P-selectin expression. Activatio n status as measured by PMN phagocytic and oxidative function were not influenced by endogenous glucocorticoid blockade. These findings sugg est that endogenous glucocorticoids selectively influence PMN migratio n to inflamed joints via P-selectin expression, but have no effect on PMN activation status.