Histamine augments cytokine-stimulated IL-11 production by human lung fibroblasts.

Histamine mediates its effects via histamine receptors and by participating in a multicellular cytokine cascade. IL-11 is a stromal cell-derived cytokine with biologic activities that overlap with IL-6. To further understand the biology of histamine and IL-11, we determined whether histamine regulates the production of IL-11 by human lung fibroblasts. Histamine was a weak stimulator of IL-11 production. Importantly, it also interacted in a synergistic fashion with TGF-beta 1 to further augment IL-11 protein production and mRNA accumulation. This synergistic interaction was not altered by the H2 receptor antagonist cimetidine and could not be reproduced with the H2 receptor agonist 4-methylhistamine. In addition, it was not abrogated by the cyclic nucleotide-dependent protein kinase inhibitor N-(2-1-guanidinoethyl)-5 isoquinolinesulfonamide hydrochloride), and histamine and TGF-beta 1 did not stimulate intracellular cAMP. In contrast, the synergy was abrogated by the H1 histamine receptor antagonists diphenhydramine and pyrilamine, could be reproduced when histamine was replaced with the H1 agonist 2-methylhistamine, and was abrogated by the calmodulin antagonists N-(6-aminohexyl)-1-napthalenesulfonamide), N-(6-aminohexyl)-5-chloro-1-napthalenesulfonamide), and trifluoperazine dichloride and by the intracellular calcium chelator 1,2-bis-(2-amino-5-bromo-phenoxy)ethane-N,N,N',N'-tetraacetic acid, tetra(acetoxymethyl)-ester. In addition, although TGF-beta 1 did not alter cytosolic Ca2+, histamine caused a biphasic increase in cytosolic Ca2+, and the majority of cells incubated with TGF-beta 1 plus histamine exhibited sustained Ca2+ oscillations. These studies demonstrate that histamine is an important regulator of fibroblast IL-11 production, that histamine interacts with TGF-beta 1 in the induction of this cytokine, and that this interaction is mediated, to a great extent, by a pretranslational mechanism that is dependent on H1 receptors and a calcium/calmodulin-dependent activation pathway.