title: Autocrine signaling by IL-10 mediates altered responsiveness of atopic sensitized airway smooth muscle.
abstract: To elucidate the role and mechanism of action of interleukin (IL)-10 in regulating airway smooth muscle (ASM) responsiveness in the atopic asthmatic state, isolated rabbit tracheal ASM segments were passively sensitized with serum from atopic asthmatic patients or nonatopic nonasthmatic (control) subjects in both the absence and presence of an anti-IL-10 receptor blocking antibody (Ab). Relative to control ASM, atopic asthmatic serum-sensitized tissues exhibited enhanced isometric constrictor responses to administered acetylcholine and attenuated the relaxation responses to isoproterenol. These proasthmatic effects were prevented in atopic asthmatic serum-sensitized ASM that was pretreated with anti-IL-10 receptor Ab. In complementary experiments, exposure of cultured human ASM cells to atopic asthmatic serum induced upregulated expression of IL-10 mRNA. Moreover, extended studies demonstrated that 1) exogenous IL-10 administration to naive ASM elicited augmented contractility to acetylcholine and impaired relaxation to isoproterenol, 2) these effects of IL-10 were prevented by pretreating the tissues with an IL-5 receptor Ab, and 3) IL-10 administration induced upregulated mRNA expression and release of IL-5 protein from cultured ASM cells. Collectively, these findings provide new evidence demonstrating that the altered responsiveness of atopic asthmatic serum-sensitized ASM is largely attributed to activation of an intrinsic T helper type 2-type autocrine mechanism involving IL-10-mediated release and the action of IL-5 in the sensitized ASM itself.
authors.affiliation: Division of Pulmonary Medicine, Joseph Stokes, Jr. Research Institute, Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA. grunstein@email.chop.edu
authors.forename: M M
authors.initials: MM
authors.lastname: Grunstein
authors.forename: H
authors.initials: H
authors.lastname: Hakonarson
authors.forename: J
authors.initials: J
authors.lastname: Leiter
authors.forename: M
authors.initials: M
authors.lastname: Chen
authors.forename: R
authors.initials: R
authors.lastname: Whelan
authors.forename: J S
authors.initials: JS
authors.lastname: Grunstein
authors.forename: S
authors.initials: S
authors.lastname: Chuang
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001249:Asthma / Q000097:blood / Q000276:immunology; D019898:Autocrine Communication; D001980:Bronchi / Q000378:metabolism*; D001993:Bronchodilator Agents / Q000494:pharmacology; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D006801:Humans; D006969:Hypersensitivity, Immediate / Q000276:immunology* / Q000503:physiopathology; D066298:In Vitro Techniques; D016753:Interleukin-10 / Q000235:genetics / Q000378:metabolism*; D015848:Interleukin-5 / Q000235:genetics / Q000378:metabolism; D007545:Isoproterenol / Q000494:pharmacology; D009130:Muscle, Smooth / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D011817:Rabbits; D018123:Receptors, Interleukin / Q000378:metabolism; D053701:Receptors, Interleukin-10; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D001993:Bronchodilator Agents; D015848:Interleukin-5; D018123:Receptors, Interleukin; D053701:Receptors, Interleukin-10; D019010:Vascular Cell Adhesion Molecule-1; D014665:Vasodilator Agents; D016753:Interleukin-10; D007545:Isoproterenol; D000109:Acetylcholine