Selective downregulation of prostaglandin E2–related pathways by the TH2 cytokine IL-13

Trudeau, John B.; Hu, Hongsheng; Chibana, Kazuyuki; Chu, Hong Wei; Westcott, Jay Y.; Wenzel, Sally E.

doi:10.1016/j.jaci.2006.01.049

Cited by 63 publications

(53 citation statements)

References 36 publications

(36 reference statements)

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“…All asthmatic subjects met American Thoracic Society criteria for asthma and ranged from mild to severe (52). Bronchoscopy with endobronchial epithelial brushing was performed as described previously (9,53). Ex vivo studies were performed as described in SI Materials and Methods.…”

Section: Methodsmentioning

confidence: 99%

15-Lipoxygenase 1 interacts with phosphatidylethanolamine-binding protein to regulate MAPK signaling in human airway epithelial cells

Zhao

O'Donnell

Balzar

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

121

125

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Epithelial 15-lipoxygenase 1 (15LO1) and activated ERK are increased in asthma despite modest elevations in IL-13. MAPK kinase (MEK)/ERK activation is regulated by interactions of Raf-1 with phosphatidylethanolamine-binding protein 1 (PEBP1). Epithelial 15LO1 generates intracellular 15-hydroxyeicosatetraenoic acid (15HETE) conjugated to phosphatidylethanolamine (PE) (15HETE-PE). We hypothesized that (i) 15LO1 and its product 15HETE-PE serve as signaling molecules interacting with PEBP1 to activate Raf-1/MEK/ERK and that (ii) this 15LO1-15HETE-PE-regulated ERK activation amplifies IL-4Rα downstream pathways. Our results demonstrate that high epithelial 15LO1 levels correlate with ERK phosphorylation ex vivo. In vitro, IL-13 induces 15LO1, which preferentially binds to PEBP1, causing PEBP1 to dissociate from Raf-1 and activate ERK. Exogenous 15HETE-PE similarly induces dissociation of PEBP1 from Raf-1 independently of IL-13/15LO1. siRNA knockdown of 15LO1 decreases the dissociation of Raf-1 from PEBP1, and the resulting lower ERK activation leads to lower downstream IL-4Rα-related gene expression. Identical proteinprotein interactions are observed in endobronchial biopsies and fresh epithelial cells from asthmatics ex vivo. Colocalization of Raf-1 to PEBP1 is low in asthmatic tissue and cells compared with normals, whereas there is striking colocalization of 15LO1 with PEBP1 in asthma. Low 15LO1 levels in normals limit its colocalization with PEBP1. The results confirm a previously unknown signaling role for 15LO1 and its PE-conjugated eicosanoid product in human airway epithelial cells. This pathway enhances critical inflammatory pathways integral to asthma pathogenesis.

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Section: Methodsmentioning

confidence: 99%

15-Lipoxygenase 1 interacts with phosphatidylethanolamine-binding protein to regulate MAPK signaling in human airway epithelial cells

Zhao

O'Donnell

Balzar

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

121

125

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“…PGE 2 is an airway smooth muscle relaxant and may have bronchoprotective and antiinfl ammatory properties. [52][53][54] Although it is reported that IL-13 inhibits PGE 2 synthetic pathways and decreases PGE 2 secretion in HBE cells, 55 a clinical study showed that cysLT and PGE 2 concentrations in sputum are higher in those with asthma than in control subjects. 56 PGE 2 also promotes cell growth in bronchial epithelial cells.…”

Section: Secretion In Goblet-enriched Cellsmentioning

confidence: 98%

Secretory Phospholipases A 2 Are Secreted From Ciliated Cells and Increase Mucin and Eicosanoid Secretion From Goblet Cells

Tanabe

Shimokawaji

Kanoh

et al. 2015

Chest

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BACKGROUND: Secretory phospholipases A 2 (sPLA 2 ) initiate the biosynthesis of eicosanoids, are increased in the airways of people with severe asthma, and induce mucin hypersecretion. We used IL-13-transformed, highly enriched goblet cells and differentiated (ciliary cellenriched) human bronchial epithelial cell culture to evaluate the relative contribution of ciliated and goblet cells to airway sPLA 2 generation and response. We wished to determine the primary source(s) of sPLA 2 and leukotrienes in human airway epithelial cells.

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“…It is noteworthy that ALI culture is the best cell culture system that mimics in vivo airway epithelial cell biology. ALI culture was performed by plating the expanded second passage of epithelial cells onto collagen-coated 12-well Transwell plates at 4 ϫ 10 4 cells/cm 2 as previously reported (20,21). After a week in the immersed culture condition, epithelial cells reached 100% confluence and were shifted to an ALI condition by reducing the apical medium volume to 50 l. From day 0 of ALI, cells were stimulated in triplicate every 48 h with the addition of IL-13 (10 ng/ml) or PBS (as a negative control) into the apical surface (50 l) and the lower chamber (1.2 ml) for 10 days.…”

Section: Air-liquid Interface (Ali) Culture Of Normal Human Primary Bmentioning

confidence: 99%

“…ALI conditions were maintained for 10 days because previous studies have demonstrated that culture for 10 days is required for the mucociliary differentiation of human airway epithelial cells. The rational for us to stimulate cells with IL-13 at 10 ng/ml is that our previous dose-response study has shown that this dose is optimal to reduce prostaglandin E synthase, an enzyme involved in antiinflammatory cascades (21).…”

Section: Air-liquid Interface (Ali) Culture Of Normal Human Primary Bmentioning

confidence: 99%

Function and Regulation of SPLUNC1 Protein in Mycoplasma Infection and Allergic Inflammation

Chu¹,

Thaikoottathil²,

Rino³

et al. 2007

The Journal of Immunology

119

150

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Respiratory infections, including Mycoplasma pneumoniae (Mp), contribute to asthma pathobiology. To date, the mechanisms underlying the increased susceptibility of asthmatics to airway Mp infection remain unclear. Short palate, lung, and nasal epithelium clone 1 (SPLUNC1) protein is a recently described large airway epithelial cell-derived molecule that was predicted to exert host defense activities. However, SPLUNC1 function and regulation in an infectious or allergic milieu are still unknown. We determined host defense and anti-inflammatory functions of SPLUNC1 protein in Mp infection and the regulation of SPLUNC1 by Mp and allergic inflammation (e.g., IL-13). SPLUNC1 function was examined in Mp or human airway epithelial cell cultures by using SPLUNC1 recombinant protein, overexpression and RNA interference. Human and mouse bronchial epithelial SPLUNC1 was examined using immunostaining, Western blotting, ELISA, laser capture microdissection, and real-time PCR. Mouse models of Mp infection and allergic inflammation and air-liquid interface cultures of normal human primary bronchial epithelial cells were used to study SPLUNC1 regulation by Mp and IL-13. We found that: 1) SPLUNC1 protein decreased Mp levels and inhibited epithelial IL-8 production induced by Mp-derived lipoproteins; 2) normal human and mouse large airway epithelial cells expressed high levels of SPLUNC1; and 3) although Mp infection increased SPLUNC1, IL-13 significantly decreased SPLUNC1 expression and Mp clearance. Our results suggest that SPLUNC1 serves as a novel host defense protein against Mp and that an allergic setting markedly reduces SPLUNC1 expression, which may in part contribute to the persistent nature of bacterial infections in allergic airways.

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Selective downregulation of prostaglandin E2–related pathways by the TH2 cytokine IL-13

Cited by 63 publications

References 36 publications

15-Lipoxygenase 1 interacts with phosphatidylethanolamine-binding protein to regulate MAPK signaling in human airway epithelial cells

15-Lipoxygenase 1 interacts with phosphatidylethanolamine-binding protein to regulate MAPK signaling in human airway epithelial cells

Secretory Phospholipases A 2 Are Secreted From Ciliated Cells and Increase Mucin and Eicosanoid Secretion From Goblet Cells

Function and Regulation of SPLUNC1 Protein in Mycoplasma Infection and Allergic Inflammation

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