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Histamine Induces Exocytosis and IL-6 Production from Human Lung Macrophages Through Interaction with H₁ Receptors¹

Massimo Triggiani^2,*, Marco Gentile^*, Agnese Secondo, Francescopaolo Granata^*, Alfonso Oriente^*, Maurizio Taglialatela, Lucio Annunziato and Gianni Marone^*

^* Division of Clinical Immunology and Allergy and Section of Pharmacology, Department of Neuroscience, University of Naples Federico II, Naples, Italy

Increasing evidence suggests that a continuous release of histamine from mast cells occurs in the airways of asthmatic patients and that histamine may modulate functions of other inflammatory cells such as macrophages. In the present study histamine (10^-9–10^-6 M) increased in a concentration-dependent fashion the basal release of -glucuronidase (EC₅₀ = 8.2 ± 3.5 x 10^-9 M) and IL-6 (EC₅₀ = 9.3 ± 2.9 x 10^-8 M) from human lung macrophages. Enhancement of -glucuronidase release induced by histamine was evident after 30 min and peaked at 90 min, whereas that of IL-6 required 2–6 h of incubation. These effects were reproduced by the H₁ agonist (6-[2-(4-imidazolyl)ethylamino]-N-(4-trifluoromethylphenyl)heptane carboxamide but not by the H₂ agonist dimaprit. Furthermore, histamine induced a concentration-dependent increase of intracellular Ca²⁺ concentrations ([Ca²⁺]_i) that followed three types of response, one characterized by a rapid increase, a second in which [Ca²⁺]_i displays a slow but progressive increase, and a third characterized by an oscillatory pattern. Histamine-induced -glucuronidase and IL-6 release and [Ca²⁺]_i elevation were inhibited by the selective H₁ antagonist fexofenadine (10^-7–10^-4 M), but not by the H₂ antagonist ranitidine. Inhibition of histamine-induced -glucuronidase and IL-6 release by fexofenadine was concentration dependent and displayed the characteristics of a competitive antagonism (K_d = 89 nM). These data demonstrate that histamine induces exocytosis and IL-6 production from human macrophages by activating H₁ receptor and by increasing [Ca²⁺]_i and they suggest that histamine may play a relevant role in the long-term sustainment of allergic inflammation in the airways.

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