Abstract

In this study, the role of histamine in interleukin-1 (IL-1) formation in murine bone marrow stromal cells was investigated in vitro. It was found that histamine and 4-methylhistamine increased the number of granulocyte colony-forming units in murine bone marrow cells. A similar effect was elicited by dibutyryl-cAMP and theophylline. When histamine and H2 agonists, such as 4-methylhistamine and dimaprit, were added to the culture medium containing murine bone marrow stromal cells, thymocyte comitogenic activity detected in the medium increased significantly. However, no such effect was observed in the case of 2-methyl-histamine, an H1 agonist. Histamine-induced production of thymocyte comitogenic activity in bone marrow stromal cells was inhibited by some H2 antagonists, such as cimetidine, ranitidine, and famotidine, but not by the H1 antagonist pyrilamine. Histamine was also effective in inducing the colony-promoting activity in murine bone marrow stromal cells. This was also inhibited by H2 antagonists such as cimetidine, ranitidine, and famotidine. Histamine elicited an increase in cAMP content in bone marrow stromal cells. From gel filtration analysis, the molecular mass of the active substance produced by bone marrow stromal cells in response to histamine was in the range of 15 to 20 kDa. By means of Western blotting analysis, it was found that production of pro-IL-1 alpha in the bone marrow stromal cells was induced by histamine. The production of pro-IL-1 alpha in bone marrow stromal cells stimulated by histamine was inhibited not only by H2 antagonists, such as cimetidine, ranitidine, and famotidine, but also by the protein kinase A antagonist KT-5720. These results indicate that histamine stimulates the production of IL-1 alpha in bone marrow stromal cells and that this results in the proliferation and differentiation of neutrophil progenitor cells.