We have examined the signal transduction pathways leading to the expression of the interleukin-1 beta (IL-1 beta) gene in human myeloid leukemia cells lines. Two cell lines representing different stages of differentiation were used (HL-60, promyelocytic, and THP-1, mature monocytic). In accordance with previous studies, it was observed that a protein kinase C (PKC) activator, phorbol myristate acetate (PMA), was a sufficient stimulus for induction of the IL-1 beta messenger RNA (mRNA) expression and IL-1 beta protein production in both of these cell lines. A structural analog of cyclic adenosine monophosphate (dbcAMP) or agents elevating the endogenous cAMP levels (prostaglandin E2, forskolin) were not alone able to induce IL-1 beta expression, but they strongly enhanced the PMA-induced IL-1 beta production and IL-1 beta mRNA accumulation. Nuclear run off analysis showed that this elevation in IL-1 beta mRNA levels was due to an increased rate of transcription. If dbcAMP was added 6 hours before PMA to the cultures, no enhancement in the IL-1 beta production was seen, implying that for this enhancing effect both of these signals must be present simultaneously. PKC inhibitor, H7, also blocked effectively the PMA plus dbcAMP induced IL-1 beta production, while the protein kinase A (PKA) inhibitor, HA1004, had no effect, suggesting that PKA activation is not involved in the mechanism of action of cAMP in this case. Collectively, the present findings show that cAMP-dependent signals can have a positive regulatory effect on the PKC-dependent activation of the IL-1 beta gene in cells derived from different stages of myeloid differentiation.