title: Stimulus-selective regulation of human mast cell gene expression, degranulation and leukotriene production by fluticasone and salmeterol.
abstract: Despite the fact that glucocorticoids and long acting beta agonists are effective treatments for asthma, their effects on human mast cells (MC) appear to be modest. Although MC are one of the major effector cells in the underlying inflammatory reactions associated with asthma, their regulation by these drugs is not yet fully understood and, in some cases, controversial. Using a human immortalized MC line (LAD2), we studied the effects of fluticasone propionate (FP) and salmeterol (SM), on the release of early and late phase mediators. LAD2 cells were pretreated with FP (100 nM), SM (1 µM), alone and in combination, at various incubation times and subsequently stimulated with agonists substance P, C3a and IgE/anti-IgE. Degranulation was measured by the release of β-hexosaminidase. Cytokine and chemokine expression were measured using quantitative PCR, ELISA and cytometric bead array (CBA) assays. The combination of FP and SM synergistically inhibited degranulation of MC stimulated with substance P (33% inhibition compared to control, n = 3, P<.05). Degranulation was inhibited by FP alone, but not SM, when MC were stimulated with C3a (48% inhibition, n = 3, P<.05). As previously reported, FP and SM did not inhibit degranulation when MC were stimulated with IgE/anti-IgE. FP and SM in combination inhibited substance P-induced release of tumor necrosis factor (TNF), CCL2, and CXCL8 (98%, 99% and 92% inhibition, respectively, n = 4, P<.05). Fluticasone and salmeterol synergistically inhibited mediator production by human MC stimulated with the neuropeptide substance P. This synergistic effect on mast cell signaling may be relevant to the therapeutic benefit of combination therapy in asthma.
authors.affiliation: National Institute for Nanotechnology, National Research Council, Edmonton, Alberta, Canada.
authors.forename: Adriana
authors.initials: A
authors.lastname: Catalli
authors.affiliation: National Institute for Nanotechnology, National Research Council, Edmonton, Alberta, Canada.
authors.forename: Victor
authors.initials: V
authors.lastname: Karpov
authors.affiliation: Northwestern University Feinberg School of Medicine, Allergy-Immunology Division, Chicago, Ilinois, United States of America.
authors.forename: Levente E
authors.initials: LE
authors.lastname: Erdos
authors.affiliation: Northwestern University Feinberg School of Medicine, Allergy-Immunology Division, Chicago, Ilinois, United States of America.
authors.forename: Brian P
authors.initials: BP
authors.lastname: Tancowny
authors.affiliation: Northwestern University Feinberg School of Medicine, Allergy-Immunology Division, Chicago, Ilinois, United States of America.
authors.forename: Robert P
authors.initials: RP
authors.lastname: Schleimer
authors.affiliation: National Institute for Nanotechnology, National Research Council, Edmonton, Alberta, Canada; Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Marianna
authors.initials: M
authors.lastname: Kulka
mesh_terms: D000420:Albuterol / Q000031:analogs & derivatives* / Q000494:pharmacology; D000730:Androstadienes / Q000494:pharmacology*; D002460:Cell Line; D000068298:Fluticasone; D006801:Humans; D015289:Leukotrienes / Q000378:metabolism*; D008407:Mast Cells / Q000187:drug effects* / Q000378:metabolism*; D000068299:Salmeterol Xinafoate
chemical_list: D000730:Androstadienes; D015289:Leukotrienes; D000068299:Salmeterol Xinafoate; D000068298:Fluticasone; D000420:Albuterol