title: Complement C3a-induced IL-17 plays a critical role in an IgE-mediated late-phase asthmatic response and airway hyperresponsiveness via neutrophilic inflammation in mice.
abstract: Allergen-specific IgE plays an essential role in the pathogenesis of allergic asthma. Although there has been increasing evidence suggesting the involvement of IL-17 in the disease, the relationship between IL-17 and IgE-mediated asthmatic responses has not yet been defined. In this study, we attempted to elucidate the contribution of IL-17 to an IgE-mediated late-phase asthmatic response and airway hyperresponsiveness (AHR). BALB/c mice passively sensitized with an OVA-specific IgE mAb were challenged with OVA intratracheally four times. The fourth challenge caused a late-phase increase in airway resistance associated with elevated levels of IL-17(+)CD4(+) cells in the lungs. Multiple treatments with a C3a receptor antagonist or anti-C3a mAb during the challenges inhibited the increase in IL-17(+)CD4(+) cells. Meanwhile, a single treatment with the antagonist or the mAb at the fourth challenge suppressed the late-phase increase in airway resistance, AHR, and infiltration by neutrophils in bronchoalveolar lavage fluid. Because IL-17 production in the lungs was significantly repressed by both treatments, the effect of an anti-IL-17 mAb was examined. The late-phase increase in airway resistance, AHR, and infiltration by neutrophils in bronchoalveolar lavage fluid was inhibited. Furthermore, an anti-Gr-1 mAb had a similar effect. Collectively, we found that IgE mediated the increase of IL-17(+)CD4(+) cells in the lungs caused by repeated Ag challenges via C3a. The mechanisms leading to the IgE-mediated late-phase asthmatic response and AHR are closely associated with neutrophilic inflammation through the production of IL-17 induced by C3a.
authors.affiliation: Department of Pharmacology, Kobe Pharmaceutical University, Higashinada, Kobe 658-8558, Japan. mizutani@kobepharma-u.ac.jp
authors.forename: Nobuaki
authors.initials: N
authors.lastname: Mizutani
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Goshima
authors.forename: Takeshi
authors.initials: T
authors.lastname: Nabe
authors.forename: Shin
authors.initials: S
authors.lastname: Yoshino
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000502:physiology; D001249:Asthma / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D016535:Bronchial Hyperreactivity / Q000276:immunology* / Q000473:pathology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D015926:Complement C3a / Q000037:antagonists & inhibitors / Q000276:immunology / Q000502:physiology*; D007073:Immunoglobulin E / Q000502:physiology*; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors / Q000276:immunology / Q000502:physiology; D020381:Interleukin-17 / Q000096:biosynthesis / Q000276:immunology / Q000502:physiology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009504:Neutrophils / Q000276:immunology* / Q000473:pathology*; D011951:Receptors, Complement / Q000037:antagonists & inhibitors; D013997:Time Factors
chemical_list: D000911:Antibodies, Monoclonal; D018836:Inflammation Mediators; D020381:Interleukin-17; D011951:Receptors, Complement; C085567:complement C3a receptor; D007073:Immunoglobulin E; D015926:Complement C3a