Histamine induces exocytosis and IL-6 production from human lung macrophages through interaction with H1 receptors.
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 beta-glucuronidase (EC(50) = 8.2 +/- 3.5 x 10(-9) M) and IL-6 (EC(50) = 9.3 +/- 2.9 x 10(-8) M) from human lung macrophages. Enhancement of beta-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 H(1) agonist (6-[2-(4-imidazolyl)ethylamino]-N-(4-trifluoromethylphenyl)heptane carboxamide but not by the H(2) agonist dimaprit. Furthermore, histamine induced a concentration-dependent increase of intracellular Ca(2+) concentrations ([Ca(2+)](i)) that followed three types of response, one characterized by a rapid increase, a second in which [Ca(2+)](i) displays a slow but progressive increase, and a third characterized by an oscillatory pattern. Histamine-induced beta-glucuronidase and IL-6 release and [Ca(2+)](i) elevation were inhibited by the selective H(1) antagonist fexofenadine (10(-7)-10(-4) M), but not by the H(2) antagonist ranitidine. Inhibition of histamine-induced beta-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 H(1) receptor and by increasing [Ca(2+)](i) and they suggest that histamine may play a relevant role in the long-term sustainment of allergic inflammation in the airways.
Division of Clinical Immunology and Allergy, University of Naples Federico II, Naples, Italy. triggian@unina.it
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D002118:Calcium / Q000378:metabolism / Q000502:physiology; D003600:Cytosol / Q000378:metabolism; D017259:Dimaprit / Q000494:pharmacology; D004306:Dose-Response Relationship, Immunologic; D005089:Exocytosis / Q000276:immunology*; D005966:Glucuronidase / Q000378:metabolism; D006632:Histamine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000502:physiology*; D017442:Histamine Agonists / Q000494:pharmacology; D006634:Histamine H1 Antagonists / Q000494:pharmacology; D006635:Histamine H2 Antagonists / Q000494:pharmacology; D006801:Humans; D015850:Interleukin-6 / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D008168:Lung / Q000166:cytology / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism*; D016676:Macrophages, Alveolar / Q000201:enzymology / Q000276:immunology / Q000378:metabolism*; D012333:RNA, Messenger / Q000096:biosynthesis; D011969:Receptors, Histamine H1 / Q000378:metabolism*; D014052:Toluidines / Q000494:pharmacology; D015854:Up-Regulation / Q000276:immunology
D017442:Histamine Agonists; D006634:Histamine H1 Antagonists; D006635:Histamine H2 Antagonists; D015850:Interleukin-6; D012333:RNA, Messenger; D011969:Receptors, Histamine H1; D014052:Toluidines; C081972:6-((2-(4-imidazolyl)ethyl)amino)heptanoic acid 4-toluidide; D006632:Histamine; D005966:Glucuronidase; D002118:Calcium; D017259:Dimaprit