PROINFLAMMATORY CYTOKINES INTERACT SYNERGISTICALLY WITH EPIDERMAL GROWTH-FACTOR TO STIMULATE PGE2 PRODUCTION IN AMNION-DERIVED CELLS

Recent evidence has implicated cytokines and growth factors in the initiation of parturition in women. In the present study, the amnion-derived cell line WISH was used to determine whether proinflammatory cytokines (interleukins 1-beta, 6, and 8, tumor necrosis factor-alpha, and granulocyte/macrophage colony stimulating factor) could amplify epidermal growth factor-induced prostaglandin E2 production. WISH cells were preincubated with cytokines (0.0001-10 ng/ml) for 60 min and then challenged with EGF (10 ng/ml) for 4 hrs after which PGE2 production was measured by radioimmunoassay. EGF, IL-1-beta and TNF-alpha alone caused a dose-dependent increase in PGE2 production, while IL-6, IL-8 and GM-CSF were ineffective over the dose range tested. When cells were preincubated with IL-1-beta or TNF-alpha, there was a dose-dependent potentiation of EGF-induced PGE2 production that was greater than the sum of EGF alone and IL-1-beta or TNF-alpha alone. In each case, the minimum dose of IL-1-beta or TNF-alpha which amplified EGF-induced PGE, production was 0.1 ng/ml (p<0.05, Student's t-test). These data show that low concentrations of IL-1-beta or TNF-alpha may serve to amplify EGF-mediated PGE2 biosynthesis in amnion-derived cells and suggest that cytokines may modulate EGF function in responsive cells.