Regulation of levels of IL-1 mRNA in human fibroblasts.

Interleukin-1 (IL-1) has a crucial role in host defenses, inflammatory processes, and tissue homeostasis. A wide variety of cells produce this protein in response to a number of extracellular stimuli including microorganisms, antigenic stimuli, and products from other cells. Regulation of IL-1 production at the molecular level is poorly understood. We studied expression, intracellular signals, and posttranscriptional regulation of IL-1 mRNA in human mesenchymal cells by using Northern blot analysis. Tumor necrosis factor alpha (TNF alpha) and activators of protein kinase C including 12-O-tetradecanoylphorbol-13-acetate (TPA) and teleocidin induced the accumulation of IL-1 beta mRNA in human fibroblasts (WI-38). Effect of TNF alpha was not blocked by inhibitors of either protein synthesis (cycloheximide) or protein kinase C activity. Accumulation of IL-1 beta mRNA was also increased by a calcium ionophore (A23187) and an inhibitor of the Na+/K+ pump (ouabain); both compounds are known to increase cytoplasmic levels of Ca++. Stability of IL-1 beta mRNA in fibroblasts exposed to TPA was more than fourfold greater than after fibroblasts were exposed to either TNF alpha or cycloheximide. This suggests that posttranscriptional stabilization of IL-1 beta mRNA is a major mechanism leading to accumulation of IL-1 beta mRNA after activation of PKC in fibroblasts. Fibroblasts did not express IL-1 alpha mRNA after exposure to stimuli which induced the accumulation of IL-1 beta mRNA. In summary, several different pathways regulate levels of IL-1 beta mRNA in human mesenchymal cells.