title: IL-12 contributes to allergen-induced airway inflammation in experimental asthma.
abstract: Lack of sufficient IL-12 production has been suggested to be one of the basic underlying mechanisms in atopy, but a potential role of IL-12 in established allergic airway disease remains unclear. We took advantage of a mouse model of experimental asthma to study the role of IL-12 during the development of bronchial inflammation. Administration of anti-IL-12p35 or anti-IL-12p40 mAb to previously OVA-sensitized BALB/c mice concomitantly with exposure to nebulized OVA, abolished both the development of bronchial hyperresponsiveness to metacholine as well as the eosinophilia in bronchoalveolar lavage fluid and peripheral blood. Anti-IL-12 treatment reduced CD4(+) T cell numbers and IL-4, IL-5, and IL-13 levels in the bronchoalveolar lavage fluid and the mRNA expression of IL-10, eotaxin, RANTES, MCP-1, and VCAM-1 in the lung. Anti-IL-12p35 treatment failed to show these effects in IFN-gamma knockout mice pointing to the essential role of IFN-gamma in IL-12-induced effects. Neutralization of IL-12 during the sensitization process aggravated the subsequent development of allergic airway inflammation. These data together with recent information on the role of dendritic cells in both the sensitization and effector phase of allergic respiratory diseases demonstrate a dual role of IL-12. Whereas IL-12 counteracts Th2 sensitization, it contributes to full-blown allergic airway disease upon airway allergen exposure in the postsensitization phase, with enhanced recruitment of CD4(+) T cells and eosinophils and with up-regulation of Th2 cytokines, chemokines, and VCAM-1. IFN-gamma-producing cells or cells dependent on IFN-gamma activity, play a major role in this unexpected proinflammatory effect of IL-12 in allergic airway disease.
authors.affiliation: Laboratory of Experimental Immunology, University Hospitals, Faculty of Medicine, Catholic University of Leuven, Herestraat 49, B-3000 Leuven, Belgium.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Meyts
authors.forename: Peter W
authors.initials: PW
authors.lastname: Hellings
authors.forename: Greet
authors.initials: G
authors.lastname: Hens
authors.forename: Bart M
authors.initials: BM
authors.lastname: Vanaudenaerde
authors.forename: Bert
authors.initials: B
authors.lastname: Verbinnen
authors.forename: Hubertine
authors.initials: H
authors.lastname: Heremans
authors.forename: Patrick
authors.initials: P
authors.lastname: Matthys
authors.forename: Dominique M
authors.initials: DM
authors.lastname: Bullens
authors.forename: Lut
authors.initials: L
authors.lastname: Overbergh
authors.forename: Chantal
authors.initials: C
authors.lastname: Mathieu
authors.forename: Kris
authors.initials: K
authors.lastname: De Boeck
authors.forename: Jan L
authors.initials: JL
authors.lastname: Ceuppens
mesh_terms: D000485:Allergens / Q000276:immunology; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D001249:Asthma / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D018925:Chemokines / Q000032:analysis / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000473:pathology; D007371:Interferon-gamma / Q000235:genetics / Q000502:physiology*; D018664:Interleukin-12 / Q000037:antagonists & inhibitors / Q000502:physiology*; D053765:Interleukin-12 Subunit p35 / Q000037:antagonists & inhibitors; D053762:Interleukin-12 Subunit p40 / Q000037:antagonists & inhibitors; D007378:Interleukins / Q000032:analysis / Q000235:genetics / Q000378:metabolism; D008168:Lung / Q000737:chemistry / Q000276:immunology* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D010047:Ovalbumin / Q000276:immunology; D011014:Pneumonia / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism; D019010:Vascular Cell Adhesion Molecule-1 / Q000032:analysis / Q000235:genetics / Q000378:metabolism
chemical_list: D000485:Allergens; D000911:Antibodies, Monoclonal; D018925:Chemokines; D053765:Interleukin-12 Subunit p35; D053762:Interleukin-12 Subunit p40; D007378:Interleukins; D012333:RNA, Messenger; D019010:Vascular Cell Adhesion Molecule-1; D018664:Interleukin-12; D007371:Interferon-gamma; D010047:Ovalbumin