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* John Curtin School of Medical Research, Australian National University, Canberra, Australia;
Department of Pathology, School of Medical Sciences, University of New South Wales, Sydney, Australia; and
Priority Research Centre for Asthma and Respiratory Disease, Faculty of Health and Hunter Medical Research Institute, University of Newcastle, Newcastle, Australia
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.
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1 This work was supported by National Health and Medical Research Peter Doherty Training Fellowship 179841 (to D.C.W.), National Health and Medical Research Council Project Grant 366765 (to D.C.W. and R.K.), and National Health and Medical Research Council Program Grant 224207 (to P.S.F.).
2 Address correspondence and reprint requests to Dr. Dianne C. Webb, Division of Molecular Bioscience, John Curtin School of Medical Research, Australian National University, Canberra, ACT, Australia 0200. E-mail: dianne.webb{at}anu.edu.au
3 Abbreviations used in this paper: DC, dendritic cell; BALF, bronchoalveolar lavage fluid; 12(S)-HETE, 12-hydroxyeicosatetraenoic acid; 12/15-LOX, 12/15-lipoxygenase; MLN, mediastinal lymph node; WT, wild type; 15(S)-HETE, 15-hydroxyeicosatetraenoic acid; HpETE, hydroxyperoxyeicosatetraenoic acid; LDL, low-density lipoprotein; PPAR
, peroxisome proliferator-activated nuclear receptor .
This article has been cited by other articles:
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  U. Mabalirajan, A. Agrawal, and B. Ghosh Comment on "Ym1/2 Promotes Th2 Cytokine Expression by Inhibiting 12/15(S)-Lipoxygenase: Identification of a Novel Pathway for Regulating Allergic Inflammation" J. Immunol., November 15, 2009; 183(10): 6039 - 6039. [Full Text] [PDF]
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D. C. Webb Response to Comment on "Ym1/2 Promotes Th2 Cytokine Expression by Inhibiting 12/15(S)-Lipoxygenaes: Identification of a Novel Pathway for Regulating Allergic Inflammation" J. Immunol., November 15, 2009; 183(10): 6039 - 6040. [Full Text] [PDF]
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