Molecular regulation of tumor necrosis factor-alpha and lymphotoxin production in T cells. Inhibition by prostaglandin E2.
The effects of prostaglandin E2 (PGE2) and other eicosanoids were determined on tumor necrosis factor-alpha (TNF-alpha) and lymphotoxin (LT; TNF-beta) production by murine Th1, antigen-specific major histocompatibility complex class II-restricted T cell clones. T cells activated with immobilized anti-CD3 or with soluble concanavalin A (ConA) produced approximately 100-1,000 units/ml TNF-alpha/LT as determined by cytotoxicity against the WEHI-164 murine fibrosarcoma cell line. TNF-alpha/LT biological activity was induced rapidly with significant production evident approximately 4 h after stimulation with either anti-CD3 or ConA. PGE2 inhibited the anti-CD3- and ConA-induced production of TNF-alpha/LT bioactivity in a dose-dependent manner. Incubation with 1 x 10(-9) M PGE2 inhibited production of TNF-alpha/LT biological activity from anti-CD-activated F1.28, or 450A.1 T cell clones by approximately 50%. Incubation with 1 x 10(-7) M PGE2 resulted in 90% inhibition of biological activity. PGE2 also inhibited both TNF-alpha and LT mRNA accumulation by more than 90%. These results suggest that the reduced production of cytotoxic activity in the presence of PGE2 was caused by the inhibition of both TNF-alpha and LT. No inhibition of T cell TNF-alpha or LT production was observed when anti-CD3- or ConA-activated cells were incubated with PGD2, PGF2 alpha, 5-hydroxyeicosatetraenoic acid or leukotriene C4. Nuclear run-on experiments indicated that the PGE2-mediated decrease of TNF-alpha and LT mRNA accumulation was caused, in part, by an inhibitory effect on the transcription of these genes. This is the first report of PGE2-mediated inhibition of TNF-alpha in T cells and PGE2-mediated inhibition of LT production in any cell type.