title: Carbon monoxide modulates the response of human basophils to FcepsilonRI stimulation through the heme oxygenase pathway.
abstract: We report the effects of exogenous and endogenous carbon monoxide (CO) on the immunological activation of human basophils. Hemin (1-100 microM), a heme oxygenase substrate analogue, significantly increased the formation of bilirubin from partially purified human basophils, thus indicating that these cells express heme oxygenase. This effect was reversed by preincubating the cells for 30 min with Zn-protoporphyrin IX (100 microM), a heme oxygenase inhibitor. Hemin (100 microM) also decreased immunoglobulin G anti-Fcepsilon (anti-IgE)-induced activation of basophils, measured by the expression of a membrane granule-associated protein, identified as cluster differentiation protein 63 (CD63), and by histamine release. These effects were reversed by Zn-protoporphyrin IX (100 microM), by oxyhemoglobin (HbO(2)), a CO scavenger (100 microM), and by 1H-[1,2,4]oxadiazolo[4,3-a] quinoxalin-1-one (ODQ), an inhibitor of the soluble guanylyl cyclase (100 microM). Exposure of basophils to exogenous CO (10 microM for 30 min) also decreased their activation, while nitrogen (N(2)) was ineffective. HbO(2) and ODQ reversed the inhibition, reversing both membrane protein CD63 expression and histamine release to basal values. Both hemin and exogenous CO significantly raised cGMP levels in basophils and blunted the rise of calcium levels caused by immunological activation. This study suggests that CO increases cGMP formation, which in turn induces a fall in intracellular Ca(2+) concentration, thereby resulting in the inhibition of human basophil activation.
authors.affiliation: Department of Preclinical and Clinical Pharmacology, University of Florence, Viale Pieraccini 6, 50139, Florence, Italy.
authors.forename: Alfredo
authors.initials: A
authors.lastname: Vannacci
authors.forename: Roberto
authors.initials: R
authors.lastname: Baronti
authors.forename: Giovanni
authors.initials: G
authors.lastname: Zagli
authors.forename: Cosimo
authors.initials: C
authors.lastname: Marzocca
authors.forename: Simone
authors.initials: S
authors.lastname: Pierpaoli
authors.forename: Daniele
authors.initials: D
authors.lastname: Bani
authors.forename: Maria Beatrice
authors.initials: MB
authors.lastname: Passani
authors.forename: Pier Francesco
authors.initials: PF
authors.lastname: Mannaioni
authors.forename: Emanuela
authors.initials: E
authors.lastname: Masini
mesh_terms: D000888:Antibodies, Anti-Idiotypic / Q000494:pharmacology; D015703:Antigens, CD / Q000096:biosynthesis; D001491:Basophils / Q000276:immunology / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D002248:Carbon Monoxide / Q000378:metabolism / Q000494:pharmacology*; D006152:Cyclic GMP / Q000378:metabolism; D005434:Flow Cytometry; D006162:Guanylate Cyclase; D006419:Heme Oxygenase (Decyclizing) / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism*; D006427:Hemin / Q000494:pharmacology; D006636:Histamine Release; D006801:Humans; D066298:In Vitro Techniques; D008854:Microscopy, Electron; D010069:Oxadiazoles / Q000494:pharmacology; D010980:Platelet Membrane Glycoproteins / Q000096:biosynthesis; D011524:Protoporphyrins / Q000494:pharmacology; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors; D017455:Receptors, IgE / Q000096:biosynthesis / Q000276:immunology / Q000378:metabolism*; D000071756:Soluble Guanylyl Cyclase; D060149:Tetraspanin 30
chemical_list: C116907:1H-(1,2,4)oxadiazolo(4,3-a)-quiloxalin-1-one; D000888:Antibodies, Anti-Idiotypic; D015703:Antigens, CD; C554586:CD63 protein, human; D010069:Oxadiazoles; D010980:Platelet Membrane Glycoproteins; D011524:Protoporphyrins; D018160:Receptors, Cytoplasmic and Nuclear; D017455:Receptors, IgE; D060149:Tetraspanin 30; C026408:anti-IgE antibodies; C017803:zinc protoporphyrin; D006427:Hemin; D002248:Carbon Monoxide; D006419:Heme Oxygenase (Decyclizing); D006162:Guanylate Cyclase; D000071756:Soluble Guanylyl Cyclase; D006152:Cyclic GMP; D002118:Calcium