Differential regulation of interleukin-6 expression in human fibroblasts by tumor necrosis factor-α and lymphotoxin

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Abstract
The treatment of human diploid fibroblasts with tumor necrosis factor (TNP)‐α and with lymphotoxin (LT) is associated with induction of interleuk‐in‐6 (IL‐6) transcripts with TNF‐α being 10‐fold more potent than LT. Here we report on the TNF‐α/LT‐induced signaling mechanisms responsible for the regulation of IL‐6 gene expression in these cells. Run‐on assays demonstrated that both TNF‐α and LT increase IL‐6 mRNA levels by transcriptional activation of this gene. Stability studies of IL‐6 transcripts in fibroblasts showed that TNF‐α delayed IL‐6 mRNA decay but not LT. The induction of IL‐6 transcripts by TNF‐α and LT was not inhibited by the isoquinoline sulfonamide derivative H7. Similarly, depletion of protein kinase C (PKC) by 12‐O‐tetradecanoyl‐phorbol 13‐acetate (TPA) did not change the ability of TNF‐α and LT to induce IL‐6 transcripts, demonstrating that stimulation by these agents may not be mediated by activation of PKC. Stimulation of IL‐6 transcripts in fibroblasts did also not require new protein synthesis as exposure to the protein synthesis inhibitor cycloheximide (CHX) enhanced accumulation of IL‐6 mRNA in the presence or absence of TNF‐α or LT.