Regulation of histamine production in macrophages

Stimulating cells of the mouse macrophage-like cell line RAW 264.7 with the Ca²⁺-ATPase inhibitor thapsigargin increased histamine production. Thapsigargin increased the levels of histidine decarbxylase (HDC) mRNA at 4 h and the expression of 74-kDa HDC protein at 8 h. PD98059, a specific inhibitor of MEK-1 which phosphorylates p44/p42 MAP kinase, strongly suppressed the thapsigargin-induced histamine production, the increase in HDC mRNA level and 74-kDa HDC protein expression. In contrast, SB203580, an inhibitor of p38 MAP kinase, showed only a partial inhibition of histamine production. TPA and LPS also induced histamine production in RAW 264.7 cells, and the histamine production induced by TPA or LPS was also inhibited by PD98059, but the effect of SB203580 was partial. The synthetic glucocorticoid dexamethasone inhibited thapsigargin-induced histamine production, 74-kDa HDC protein expression and the activation of p44/p42 MAP kinases. In conclusion, the increase in histamine production in macrophages stimulated with inflammatory stimulants is due to the increased expression of 74-kDa HDC, which is positively regulated by activated p44/p42 MAP kinases. Dexamethasone inhibits thapsigargin-induced HDC protein expression and histamine production by inhibiting the MAP kinase activation.