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: Yeping Cai, Rakesh K Kumar, Jiansheng Zhou, Paul S Foster, Dianne C Webb
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 182 Issue 9 Pg. 5393-9 (May 01 2009) ISSN: 1550-6606 [Electronic] United States
• PMID: 19380786 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 12-15-lipoxygenase
• Cytokines
• Inflammation Mediators
• Interleukin-13
• Lectins
• Lipoxygenase Inhibitors
• Arachidonate 12-Lipoxygenase
• Arachidonate 15-Lipoxygenase
• Chitinases
• Ym2 protein, mouse
• Chil3 protein, mouse
• beta-N-Acetylhexosaminidases

Topics

• Animals
• Arachidonate 12-Lipoxygenase (metabolism)
• Arachidonate 15-Lipoxygenase (metabolism)
• CD4-Positive T-Lymphocytes (immunology, metabolism, pathology)
• Cells, Cultured
• Chitinases (biosynthesis, genetics, physiology)
• Coculture Techniques
• Cytokines (antagonists & inhibitors, biosynthesis)
• Dendritic Cells (immunology, metabolism, pathology)
• Eosinophilia (enzymology, pathology, prevention & control)
• Inflammation Mediators (physiology)
• Interleukin-13 (deficiency, genetics, physiology)
• Lectins (biosynthesis, genetics, physiology)
• Lipoxygenase Inhibitors
• Mice
• Mice, Inbred BALB C
• Mice, Knockout
• Signal Transduction (immunology)
• Th2 Cells (enzymology, immunology, pathology)
• beta-N-Acetylhexosaminidases (biosynthesis, genetics, physiology)