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

AbstractThe 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

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xi, 370 p. : ill. ; 24 c