PROSTAGLANDIN E(2) ENHANCES INTERLEUKIN-8 (IL-8) AND IL-6 BUT INHIBITS GMCSF PRODUCTION BY IL-1 STIMULATED HUMAN SYNOVIAL FIBROBLASTS IN-VITRO

Objective. To examine in vitro the effect of prostaglandin E(2) (PGE(2 )) on synovial cell cytokine production. Methods. Human synovial fibro blasts were stimulated with PGE(2) alone or PGE(2) in combination with interleukin 1 alpha (IL-1 alpha) (5 ng/ml) and/or indomethacin (10(-6 ) M) and assessed for the production of IL-8, IL-6, and granulocyte ma crophage colony stimulating factor (GMCSF) at the protein and messenge r RNA (mRNA) levels. Results. PGE(2) alone had Little detectable effec t on IL-8 or GMCSF; however, a small enhancement of both IL-6 mRNA and protein levels was seen. While all cytokines were markedly stimulated by IL-1 alpha, coaddition of the cyclooxygenase inhibitor indomethaci n enhanced IL-8 and GMCSF levels, but caused a reduction in IL-6 expre ssion. The addition of PGE(2) to cultures stimulated with IL-1 alpha a nd indomethacin resulted in increases in IL-6 mRNA and protein express ion while causing a concomitant reduction in GMCSF protein and mRNA ex pression. PGE(2) and illoprost (PGI(2) analog) enhanced IL-8 productio n in stimulated cells. Conclusion. While PGE(2) alone has limited effe cts on synovial cell production of IL-8 and GMCSF its effects are sign ificant in context of UL-1 alpha stimulation; endogenous PGE(2) may al ter cytokines secreted by mesenchymally derived cells. PGE(2) may be a n important modulator of cytokine driven inflammation.