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Clin Exp Allergy. 2008 Jan;38(1):113-21. Epub 2007 Nov 19.

Leukotriene D4-induced, epithelial cell-derived transforming growth factor beta1 in human bronchial smooth muscle cell proliferation.

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1
Department of Pediatrics, Immunology Division, Faculty of Medicine, Université de Sherbrooke, Sherbrooke, QC, Canada.

Abstract

BACKGROUND:

Cysteinyl-leukotrienes (cys-LTs) orchestrate many pathognomonic features of asthma in animal models of allergic airway inflammation, including bronchial smooth muscle cell (BSMC) hyperplasia. However, because cys-LTs alone do not induce mitogenesis in monocultures of human BSMC, the effect observed in vivo seemingly involves indirect mechanisms, which are still undefined.

OBJECTIVE:

This study aims to investigate the regulatory role of leukotriene (LT)D(4) on TGF-beta1 expression in airway epithelial cells and the consequence of this interplay on BSMC proliferation.

METHODS:

HEK293 cells stably transfected with cys-LT receptor 1 (CysLT1) (293LT1) were stimulated with LTD(4) and TGF-beta1 mRNA and protein expression was measured using Northern blot and ELISA, respectively. Conditioned medium (CM) harvested from LTD(4)-treated cells was then assayed for its proliferative effect on primary human BSMC. TGF-beta1 mRNA expression was also determined in tumoural type II pneumocytes A549 and in normal human bronchial epithelial cells (NHBE) following LTD(4) stimulation.

RESULTS:

The results demonstrated that LTD(4)-induced TGF-beta1 mRNA production in a time- and concentration-dependent manner in 293LT1. TGF-beta1 secretion was also up-regulated and CM from LTD(4)-treated 293LT1 was shown to increase BSMC proliferation in a TGF-beta1-dependent manner. The increased expression of TGF-beta1 mRNA by LTD(4) also occured in A549 and NHBE cells via a CysLT1-dependent mechanism.

CONCLUSION:

In conclusion, elevated expression of cys-LTs in asthmatic airways might contribute to BSMC hyperplasia and concomitant clinical features of asthma such as airway hyperresponsiveness via a paracrine loop involving TGF-beta1 production by airway epithelial cells.

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