title: Ym1/2 promotes Th2 cytokine expression by inhibiting 12/15(S)-lipoxygenase: identification of a novel pathway for regulating allergic inflammation.
abstract: The Ym1/2 lectin is expressed abundantly in the allergic mouse lung in an IL-13-dependent manner. However, the role of Ym1/2 in the development of allergic airways disease is largely unknown. In this investigation, we show that treatment of mice with anti-Ym1/2 Ab during induction of allergic airways disease attenuated mediastinal lymph node production of IL-5 and IL-13. Ym1/2 was found to be expressed by dendritic cells (DCs) in an IL-13-dependent manner and supplementation of DC/CD4(+) T cell cocultures with Ym1/2 enhanced the ability of IL-13(-/-) DCs to stimulate the secretion of IL-5 and IL-13. Affinity chromatography identified 12/15(S)-lipoxygenase (12/15-LOX) as a Ym1/2-interacting protein and functional studies suggested that Ym1/2 promoted the ability of DCs to stimulate cytokine production by inhibiting 12/15-LOX-mediated catalysis of 12-hydroxyeicosatetraenoic acid (12(S)-HETE). Treatment of DC/CD4(+) T cell cultures with the 12/15-LOX inhibitor baicalein enhanced, whereas 12(S)-HETE inhibited the production of Th2 cytokines. Notably, delivery of 12(S)-HETE to the airways of mice significantly attenuated the development of allergic airways inflammation and the production of IL-5 and IL-13. In summary, our results suggest that production of Ym1/2 in response to IL-13 promotes Th2 cytokine production and allergic airways inflammation by inhibiting the production of 12(S)-HETE by 12/15-LOX.
authors.affiliation: John Curtin School of Medical Research, Australian National University, Canberra, Australia.
authors.forename: Yeping
authors.initials: Y
authors.lastname: Cai
authors.forename: Rakesh K
authors.initials: RK
authors.lastname: Kumar
authors.forename: Jiansheng
authors.initials: J
authors.lastname: Zhou
authors.forename: Paul S
authors.initials: PS
authors.lastname: Foster
authors.forename: Dianne C
authors.initials: DC
authors.lastname: Webb
mesh_terms: D000818:Animals; D001092:Arachidonate 12-Lipoxygenase / Q000378:metabolism; D001093:Arachidonate 15-Lipoxygenase / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D002688:Chitinases / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D018920:Coculture Techniques; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D004802:Eosinophilia / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control*; D018836:Inflammation Mediators / Q000502:physiology*; D018793:Interleukin-13 / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D037102:Lectins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D016859:Lipoxygenase Inhibitors; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D015398:Signal Transduction / Q000276:immunology*; D018418:Th2 Cells / Q000201:enzymology / Q000276:immunology* / Q000473:pathology; D001619:beta-N-Acetylhexosaminidases / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*
chemical_list: C475064:12-15-lipoxygenase; D016207:Cytokines; D018836:Inflammation Mediators; D018793:Interleukin-13; D037102:Lectins; D016859:Lipoxygenase Inhibitors; D001092:Arachidonate 12-Lipoxygenase; D001093:Arachidonate 15-Lipoxygenase; D002688:Chitinases; C525260:Ym2 protein, mouse; C429541:Chil3 protein, mouse; D001619:beta-N-Acetylhexosaminidases