Influence of prostaglandin E2 and indomethacin on interferon-gamma production by cultured peripheral blood leukocytes of multiple sclerosis patients and healthy donors.

The addition of indomethacin to concanavalin A (Con A)-induced cultures of human peripheral blood leukocytes (PBL) caused an increase in interferon response, regardless of whether the PBLs were derived from multiple sclerosis (MS) patients or from control donors. Specifically the response rates increased from 71 to 100% in controls and from 24 to 53% in MS patient-derived cultures. The amounts of interferon produced also increased in both groups by 0.8 log U/ml. However, interferon yields of nonresponsive cultures becoming interferon-producing only after indomethacin treatment remained relatively low. In control cultures, maximal increases of interferon production were obtained with doses of 0.05 to 0.1 microgram/ml indomethacin; for MS patients higher doses were needed--0.1 to 0.5 microgram/ml. Conversely, a relatively low dose (0.05 microgram/ml) of exogenous prostaglandin E2 (PGE2) was able to inhibit interferon production completely in MS patient-derived cultures, whereas in control cultures higher doses were needed (0.1 to 1.0 microgram/ml). Analysis of endogenous PGE2 levels in the PBL cultures revealed that PGE2 production was similar in nonresponder MS cultures and responder control cultures but that MS leukocytes were more sensitive to the inhibitory effect of PGE2 on interferon production. We conclude that in a minor percentage of MS patient-derived PBL cultures, the deficiency in interferon-gamma (IFN-gamma) production can be (partially) overcome by treatment of the cells with indomethacin. However, in the major part of nonresponder MS cultures, indomethacin has no effect, indicating that the PG system is not the major cause for the defective interferon response in MS.