Nonsteroidal anti-inflammatory drugs (NSAIDs) are well known as immunoregulators, but the mechanisms of their action are not fully explained by the inhibition of PG synthesis. We have investigated the effect of NSAIDs on cytokine production in human PBMC and T cell clones (TCC). NSAIDs up-regulated TNF, IFN-gamma and IL-2 production at both the mRNA and protein levels, and IL-12 expression at the mRNA level. In contrast, NSAIDs down-regulated IL-6 production both at the mRNA and protein levels, and down-regulated IL-4 mRNA expression. The modulation at the mRNA level became detectable 1 h after culture. This modulation was also observed at the level of TCC. Indomethacin (IM) enhanced TNF production in all the eight TCC that were established from a patient with human T lymphotrophic virus type 1 uveitis or pulmonary sarcoidosis, and suppressed IL-6 production in six of the eight TCC, without affecting their low levels of PGE2 production. IM also enhanced TNF and suppressed IL-6 production, respectively, in both IL-2-activated PBMC and IL-2-dependent NK cell line, with the inhibition of their high levels of PGE2 production. Culture with PGE2 alone suppressed TNF production by three of the six TCC and NK cell lines, which was neutralized by addition of IM. It had, however, no effect on TNF production by the remaining three TCC or IL-2-activated PBMC. The effects of PGE2 on IL-6 production also varied among TCC.(ABSTRACT TRUNCATED AT 250 WORDS)