12/15-Lipoxygenase deficiency protects mice from allergic airways inflammation and increases secretory IgA levels

Hajek, Amanda R; Lindley, Alexa; Favoreto, Sílvio; Carter, Roderick; Schleimer, Robert P.; Kuperman, Douglas A.

doi:10.1016/j.jaci.2008.06.021

Cited by 68 publications

(66 citation statements)

References 32 publications

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“…E1 in Ref. 24), these data suggest that 15(S)-HETE is also partially produced from non-12/ 15-LOX sources in our culture systems.…”

Section: Discussionsupporting

confidence: 61%

“…Although recent studies have suggested that products of the 12/ 15-LOX biosynthetic pathway may contribute to allergic airway inflammation (24,34), these studies are confounded by the use of 12/15-LOX Ϫ/Ϫ mice in which the deficiency in 12/15-LOX stimulates a default pathway that channels arachidonic acid through the 5-LOX pathway with subsequent up-regulation of proinflammatory cysteinyl leukotrienes (24,35). Additionally, it is likely that 12/15-LOX Ϫ/Ϫ mice are deficient in a complex mixture of lipid mediators that mediate both pro-and anti-inflammatory pathways.…”

Section: Discussionmentioning

confidence: 99%

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Ym1/2 Promotes Th2 Cytokine Expression by Inhibiting 12/15(S)-Lipoxygenase: Identification of a Novel Pathway for Regulating Allergic Inflammation

Cai

Kumar

Zhou

et al. 2009

The Journal of Immunology

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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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“…E1 in Ref. 24), these data suggest that 15(S)-HETE is also partially produced from non-12/ 15-LOX sources in our culture systems.…”

Section: Discussionsupporting

confidence: 61%

Section: Discussionmentioning

confidence: 99%

Ym1/2 Promotes Th2 Cytokine Expression by Inhibiting 12/15(S)-Lipoxygenase: Identification of a Novel Pathway for Regulating Allergic Inflammation

Cai

Kumar

Zhou

et al. 2009

The Journal of Immunology

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“…High mucosal SIgA levels could possibly interfere with the interaction between allergen and IgE antibodies in sensitized individuals, thereby preventing triggering of allergic inflammation and clinical symptoms. This notion is supported by animal models showing that mucosal IgA responses inhibit airway reactivity in sensitized mice (27)(28)(29). Also, induction of IgA to allergens during immunotherapy has been suggested to relate to the development of tolerance (30).…”

Section: Discussionmentioning

confidence: 89%

Slow Salivary Secretory IgA Maturation May Relate to Low Microbial Pressure and Allergic Symptoms in Sensitized Children

et al. 2011

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“…16 Interestingly, after allergen exposure, Alox15 knockout mice had a markedly decreased number of eosinophils and did not produce specific IgE antibodies. 17 This suggests that ALOX15 activity is required for the development of sensitization during asthma. Although the significance of increased expression of ALOX15 in patients with eosinophilic esophagitis is currently unknown, it is possible that it has a role in allergen sensitization similar to that in asthma.…”

Section: A Matoso Et Almentioning

confidence: 99%

Expression microarray analysis identifies novel epithelial-derived protein markers in eosinophilic esophagitis

Matoso

Mukkada

et al. 2013

Modern Pathology

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Gene expression studies in eosinophilic esophagitis support an immune-mediated etiology associated with differential regulation of inflammatory and epithelial-derived genes. We aimed to further characterize epithelial gene expression alterations in eosinophilic esophagitis and to explore the use of immunohistochemistry to identify these alterations. Esophageal biopsies from pediatric patients with eosinophilic esophagitis before and after therapy with topical steroids (N ¼ 7) were screened by gene expression microarray and results were validated by RT-PCR. A larger group of eosinophilic esophagitis patients (N ¼ 42) was then used to evaluate protein expression by immunohistochemistry compared with reflux patients (N ¼ 15) and normal controls (N ¼ 17). Microarray and RT-PCR studies identified overexpression of ALOX15 and tumor necrosis factor alphainduced factor 6 (TNFAIP6) and underexpression of filaggrin (FLG), SLURP1 and cysteine-rich secretory protein 3 (CRISP3) in eosinophilic esophagitis. Immunohistochemistry for ALOX15 was positive in 95% of eosinophilic esophagitis and negative in all controls, all eosinophilic esophagitis after therapy and all reflux biopsies (Po0.001). TNFAIP6 was positive in 88% of eosinophilic esophagitis samples versus 47% of controls, 29% of eosinophilic esophagitis after therapy and 40% of reflux samples (P ¼ 0.002). Overexpression of both ALOX15 and TNFAIP6 directly correlated with the degree of eosinophilic infiltration. FLG was positive in 88% of controls and 100% of reflux biopsies, but negative in all eosinophilic esophagitis samples, and its expression was regained in 86% of eosinophilic esophagitis after therapy patients (Po0.001). SLURP1 expression was positive in all controls and reflux samples, but only positive in 5% of eosinophilic esophagitis and was re-expressed to 100% positivity in eosinophilic esophagitis after therapy patients (Po0.001). The majority of controls (89%) and reflux biopsies (100%) were positive for CRISP3 while eosinophilic esophagitis before therapy were positive in 14% of samples (Po0.001) with partial recovery after treatment (43%, P ¼ 0.105). This study identified five epithelial-derived markers differentially expressed in eosinophilic esophagitis easily detectable by immunohistochemistry with potential diagnostic utility.

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12/15-Lipoxygenase deficiency protects mice from allergic airways inflammation and increases secretory IgA levels

Abstract: Background-Induction of 15-lipoxygenase-1 (15-LO-1) has been observed in the airways of subjects with asthma, although its physiologic role in the airways has remained largely undefined.

Cited by 68 publications

References 32 publications

Ym1/2 Promotes Th2 Cytokine Expression by Inhibiting 12/15(S)-Lipoxygenase: Identification of a Novel Pathway for Regulating Allergic Inflammation

Ym1/2 Promotes Th2 Cytokine Expression by Inhibiting 12/15(S)-Lipoxygenase: Identification of a Novel Pathway for Regulating Allergic Inflammation

Slow Salivary Secretory IgA Maturation May Relate to Low Microbial Pressure and Allergic Symptoms in Sensitized Children

Expression microarray analysis identifies novel epithelial-derived protein markers in eosinophilic esophagitis

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