Although tumor necrosis factor (TNF) and interleukin-1 (IL) induce the expression of the IL-8, TNF-stimulated gene 6, and plasminogen activation inhibitor-2 genes and the activation of NF-kappa B with nearly identical kinetics, the two cytokines differ significantly in the induction of the IL-6 gene in all primary fibroblasts tested. IL-1 induces IL-6 gene expression after 30 min of IL-1 treatment, reaching a maximum level by 7 h, and is sustained for up to 14 h. TNF also induces the IL-6 gene expression at 30 min but the induction was low. A similar differences in the amount of IL-6 secreted was observed in the IL-1/TNF-treated cells. Measurement of IL-6 gene transcription by nuclear run-on transcription assays indicated a 4-fold higher rate of IL-6 gene transcription in IL-1-treated than in TNF-treated cells. The IL-1-induced IL-6 mRNA has a significantly longer half-life (> 6 h) compared to 30 min for TNF-treated cells. These results suggest that the induction of the IL-6 gene expression in primary human fibroblasts by TNF and IL-1 is differentially regulated at the transcriptional as well as at the post-transcriptional level.