HISTAMINE AUGMENTS CYTOKINE-STIMULATED IL-11 PRODUCTION BY HUMAN LUNGFIBROBLASTS

Histamine mediates its effects via histamine receptors and by particip ating in a multicellular cytokine cascade. IL-11 is a stromal cell-der ived cytokine with biologic activities that overlap with IL-6. To furt her understand the biology of histamine and IL-11, we determined wheth er histamine regulates the production of IL-11 by human lung fibroblas ts. Histamine was a weak stimulator of IL-11 production. Importantly, it also interacted in a synergistic fashion with TGF-beta(1) to furthe r augment IL-11 protein production and mRNA accumulation. This synergi stic interaction was not altered by the H-2 receptor antagonist cimeti dine and could not be reproduced with the H-2 receptor agonist 4-methy lhistamine, In addition, it was not abrogated by the cyclic nucleotide -dependent protein kinase inhibitor N-(2-1-guanidinoethyl)-5 isoquinol inesulfonamide hydrochloride), and histamine and TGF-beta(1) did not s timulate intracellular cAMP. In contrast, the synergy was abrogated by the H-1 histamine receptor antagonists diphenhydramine and pyrilamine , could be reproduced when histamine was replaced with the H-1 agonist 2-methylhistamine, and was abrogated by the calmodulin antagonists N- (6-aminohexyl)-1-napthalenesulfonamide), -(6-aminohexyl)-5-chloro-1-na pthalenesulfonamide), and trifluoperazine dichloride and by the intrac ellular calcium chelator 1,2-bis-(2-amino-5-bromo-phenoxy)ethane-N aci d, tetra(acetoxymethyl)-ester. In addition, although TGF-beta(1) did n ot alter cytosolic Ca2+, histamine caused a biphasic increase in cytos olic Ca2+, and the majority of cells incubated with TGF-beta(1), plus histamine exhibited sustained Ca2+ oscillations. These studies demonst rate that histamine is an important regulator of fibroblast IL-11 prod uction, that histamine interacts with TGF-beta(1) in the induction of this cytokine; and that this interaction is mediated, to a great exten t, by a pretranslational mechanism that is dependent on H-1 receptors and a calcium/calmodulin-dependent activation pathway.