title: A novel role of cysteinyl leukotrienes to promote dendritic cell activation in the antigen-induced immune responses in the lung.
abstract: Although the critical role of cysteinyl leukotrienes (cysLTs) in the inflammation, especially eosinophilic lung inflammation, in asthma has been well documented, their role in the early stage of Ag-specific immune response has not been completely clarified. In the present study, with a mouse model of asthma and in vitro studies we demonstrated that cysLTs potentiated dendritic cell (DC) functions such as Ag-presenting capacity and cytokine production. The cysLT-1 receptor antagonist (LTRA) strongly suppressed the activation of these DC functions and led to inhibition of subsequent not only Th2, but also Th1, responses in the early stage of immune response. Moreover, treatment with LTRA during the early stage of the immune response potently suppressed the development of Ag inhalation-induced eosinophilic airway inflammation, mucus production, and airway hyper-reactivity in vivo. Treatment with LTRA significantly increased PGE(2) production in the lung, and treatment with the cyclooxygenase inhibitor indomethacin abolished LTRA's suppressive effect on DCs and deteriorated the Th2 and Th1 responses and airway inflammation. With in vitro studies, we also confirmed that cysLTs production by DCs increased with LPS stimulation, and that LTRA directly suppressed the alloantigen-presenting capacity of DCs. These results suggested that cysLTs potentiate DC functions both in vivo and in vitro, and that LTRA could be beneficial to suppress the initial immune response in many immune-mediated disorders beyond asthma.
authors.affiliation: Pulmonary Division, Department of Allergy and Rheumatology, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
authors.forename: Katsuhide
authors.initials: K
authors.lastname: Okunishi
authors.forename: Makoto
authors.initials: M
authors.lastname: Dohi
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Nakagome
authors.forename: Ryoichi
authors.initials: R
authors.lastname: Tanaka
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Yamamoto
mesh_terms: D000276:Adjuvants, Immunologic / Q000494:pharmacology / Q000502:physiology*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage; D000941:Antigens / Q000008:administration & dosage* / Q000276:immunology; D001094:Arachidonate 5-Lipoxygenase / Q000172:deficiency / Q000235:genetics; D016535:Bronchial Hyperreactivity / Q000276:immunology / Q000473:pathology / Q000517:prevention & control; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D002478:Cells, Cultured; D002867:Chromones / Q000008:administration & dosage; D003545:Cysteine / Q000502:physiology*; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism*; D007249:Inflammation / Q000276:immunology / Q000517:prevention & control; D020024:Leukotriene Antagonists / Q000008:administration & dosage; D015289:Leukotrienes / Q000502:physiology*; D008168:Lung / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000037:antagonists & inhibitors; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010047:Ovalbumin / Q000008:administration & dosage / Q000276:immunology; D018077:Receptors, Leukotriene; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism
chemical_list: D000276:Adjuvants, Immunologic; D000894:Anti-Inflammatory Agents, Non-Steroidal; D000941:Antigens; D002867:Chromones; D020024:Leukotriene Antagonists; D015289:Leukotrienes; D008565:Membrane Proteins; D018077:Receptors, Leukotriene; C112381:cysteinyl-leukotriene; D010047:Ovalbumin; D001094:Arachidonate 5-Lipoxygenase; D003545:Cysteine; C083169:leukotriene D4 receptor; C047681:pranlukast