Elevation of intracellular cAMP has been associated with the suppression of macrophage activation. The present study has examined the effects of agents that alter intracellular levels of cAMP on LPS-induced macrophage gene expression. Treatment of murine peritoneal macrophages with trace amounts of LPS leads to dramatically enhanced expression of multiple mRNA including the competence genes JE and KC, first observed in platelet-derived growth factor-stimulated fibroblasts, and those encoding the inflammatory monokines IL-1 and TNF. If macrophages are first treated with cholera toxin or dibutyryl cAMP 15 min before stimulation with LPS, the accumulation of mRNA encoding both JE and TNF is strongly suppressed whereas mRNA levels for KC and IL-1 are unaffected. The suppression of JE and TNF mRNA levels is dose dependent, in the range of 10 to 500 microM dibutyryl cAMP; concentrations as high as 1 mM do not affect the expression of either KC or IL-1. When dibutyryl cAMP is added to macrophages after initiation of LPS treatment, suppressive effects are diminished in a time-dependent fashion. Furthermore, dibutyryl cAMP suppresses the LPS-induced transcriptional activation of the TNF gene. Previous work has shown that the LPS-induced expression of JE appears to be mediated by hydrolysis of polyphosphoinositides and involves a post-transcriptional mechanism. Treatment with dibutyryl cAMP suppresses JE expression induced by treatment with phorbol ester and A23187 suggesting that inhibition of gene expression must act at a site other than the initial transmembrane signaling event. Finally, dibutyryl cAMP only marginally affects the constitutive transcription of the JE gene indicating that suppression may involve a post-transcriptional mechanism. These results indicate that expression of genes encoding inducible early proteins and inflammatory monokines are selectively regulated by elevation of intracellular cAMP. Such effects may be pleiotropic in nature involving multiple molecular mechanisms.