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PLoS By Category | Recent PLoS Articles
Biochemistry - Biophysics - Immunology - Physiology - Respiratory Medicine

Leukotriene D4 and Interleukin-13 Cooperate to Increase the Release of Eotaxin-3 by Airway Epithelial Cells
Published: Friday, August 31, 2012
Author: Véronique Provost et al.

by Véronique Provost, Anick Langlois, François Chouinard, Marek Rola-Pleszczynski, Jamila Chakir, Nicolas Flamand, Michel Laviolette

Introduction

Airway epithelial cells play a central role in the physiopathology of asthma. They release eotaxins when treated with TH2 cytokines such as interleukin (IL)-4 or IL-13, and these chemokines attract eosinophils and potentiate the biosynthesis of cysteinyl leukotrienes (cysLTs), which in turn induce bronchoconstriction and mucus secretion. These effects of cysLTs mainly mediated by CysLT1 and CysLT2 receptors on epithelial cell functions remain largely undefined. Because the release of inflammatory cytokines, eotaxins, and cysLTs occur relatively at the same time and location in the lung tissue, we hypothesized that they regulate inflammation cooperatively rather than redundantly. We therefore investigated whether cysLTs and the TH2 cytokines would act in concert to augment the release of eotaxins by airway epithelial cells.

Methods

A549 cells or human primary bronchial epithelial cells were incubated with or without IL-4, IL-13, and/or LTD4. The release of eotaxin-3 and the expression of cysLT receptors were assessed by ELISA, RT-PCR, and flow cytometry, respectively.

Results

IL-4 and IL-13 induced the release of eotaxin-3 by airway epithelial cells. LTD4 weakly induced the release of eotaxin-3 but clearly potentiated the IL-13-induced eotaxin-3 release. LTD4 had no effect on IL-4-stimulated cells. Epithelial cells expressed CysLT1 but not CysLT2. CysLT1 expression was increased by IL-13 but not by IL-4 and/or LTD4. Importantly, the upregulation of CysLT1 by IL-13 preceded eotaxin-3 release.

Conclusions

These results demonstrate a stepwise cooperation between IL-13 and LTD4. IL-13 upregulates CysLT1 expression and consequently the response to cysLTs This results in an increased release of eotaxin-3 by epithelial cells which at its turn increases the recruitment of leukocytes and their biosynthesis of cysLTs. This positive amplification loop involving epithelial cells and leukocytes could be implicated in the recruitment of eosinophils observed in asthmatics.

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