Histamine Modulates the Expression of c-fosthrough Cyclic AMP Production via the H2 Receptor in the Human Promonocytic Cell Line U937

We examined the effects of histamine and its agonists on the expression of the c- fos and c- myc proto-oncogenes at the transcriptional and translational levels in the human promonocytic U937 cell line. Histamine transiently increased cAMP and c- fos expression through H 2 receptors. Dibutyryl cAMP also increased c-fos mRNA and protein, and levels remained elevated even after 12 hr of treatment. Dose-dependence studies using histamine and dimaprit showed that the EC 50 values for cAMP production and c- fos increase were similar, suggesting that cAMP might be involved in c- fos induction via H 2 receptors. Furthermore, studies carried out using H7, a protein kinase A/protein kinase C inhibitor, blocked c- fos induction, whereas no effect was observed with bisindolylmaleimide, a specific protein kinase C inhibitor. No modification of c- myc expression could be detected on treatment with histamine or its analogues. Nevertheless, dibutyryl cAMP induced a down-regulation of the levels of this proto-oncogene. In addition, dibutyryl cAMP inhibited cell growth in a dose-dependent manner, whereas histamine failed to affect proliferation and differentiation of U937 cells. Cells pretreated with dimaprit showed a decrease in the cAMP response to subsequent addition of H 2 agonists, whereas the cAMP response to prostaglandin E 2 remained unaltered. This homologous mechanism of H 2 receptor desensitization was time dependent. These results indicate that histamine activates several mechanisms involved in the induction of differentiation, such as cAMP and c- fos production, but fails to promote differentiation of U937 cells, apparently due to the rapid desensitization of H 2 receptors.