Tumor necrosis factor increases stability of interleukin-1 mRNA by activating protein kinase C.

The mRNAs coding for interleukin-1 alpha (IL-1 alpha) and IL-1 beta are constitutively transcribed but do not accumulate in human diploid fibroblasts and in fibrosarcoma cells. Treatment of these cells with tumor necrosis factor (TNF) induces accumulation of IL-1 mRNA by an unknown mechanism. This induction of IL-1 mRNA was investigated in HT-1080 cells. The induction was quite fast, with maximum levels of IL-1 alpha and beta mRNA reached 4 h after addition of TNF. Nuclear run-off experiment showed that TNF did not increase the rate of transcription of IL-1 mRNA. This mRNA was apparently unstable in untreated cells, but it accumulated in cycloheximide-treated cells. Phorbol esters induced IL-1 mRNA, suggesting that activation of protein kinase C was responsible for the accumulation of this mRNA. This hypothesis was confirmed by experiments with the PKC inhibitors staurosporine and calphostin C, which prevented the induction of IL-1 mRNA by TNF and accelerated the decay of this mRNA in cells pretreated with TNF. Both IL-1 alpha and IL-1 beta were detected in TNF-treated cells by Western blot analysis and enzyme-linked immunosorbent assay. These results indicate that the TNF-mediated induction of IL-1 can be entirely accounted for by stabilization of this mRNA.