Differential effects of simvastatin on IL-13-induced cytokine gene expression in primary mouse tracheal epithelial cells

Amir A Zeki,Reen Wu,Phil Thai,Nicholas J Kenyon

doi:10.1186/1465-9921-13-38

Abstract

BackgroundAsthma causes significant morbidity worldwide in adults and children alike, and incurs large healthcare costs. The statin drugs, which treat hyperlipidemia and cardiovascular diseases, have pleiotropic effects beyond lowering cholesterol, including immunomodulatory, anti-inflammatory, and anti-fibrotic properties which may benefit lung health. Using an allergic mouse model of asthma, we previously demonstrated a benefit of statins in reducing peribronchiolar eosinophilic inflammation, airway hyperreactivity, goblet cell hyperplasia, and lung IL-4 and IL-13 production.ObjectivesIn this study, we evaluated whether simvastatin inhibits IL-13-induced pro-inflammatory gene expression of asthma-related cytokines in well-differentiated primary mouse tracheal epithelial (MTE) cell cultures. We hypothesized that simvastatin reduces the expression of IL-13-inducible genes in MTE cells.MethodsWe harvested tracheal epithelial cells from naïve BALB/c mice, grew them under air-liquid interface (ALI) cell culture conditions, then assessed IL-13-induced gene expression in MTE cells using a quantitative real-time PCR mouse gene array kit.ResultsWe found that simvastatin had differential effects on IL-13-mediated gene expression (inhibited eotaxin-1; MCP-1,-2,-3; and osteopontin (SPP1), while it induced caspase-1 and CCL20 (MIP-3α)) in MTE cells. For other asthma-relevant genes such as TNF, IL-4, IL-10, CCL12 (MCP-5), CCL5 (RANTES), and CCR3, there were no significant IL-13-inducible or statin effects on gene expression.ConclusionsSimvastatin modulates the gene expression of selected IL-13-inducible pro-inflammatory cytokines and chemokines in primary mouse tracheal epithelial cells. The airway epithelium may be a viable target tissue for the statin drugs. Further research is needed to assess the mechanisms of how statins modulate epithelial gene expression.

Highlights

Asthma is a leading cause of morbidity worldwide affecting children and adults alike
We found that simvastatin had differential effects on IL-13-mediated gene expression (inhibited eotaxin-1; Monocyte chemotactic protein (MCP)-1,2,3; and osteopontin (SPP1), while it induced caspase-1 and CCL20 (MIP-3α)) in mouse tracheal epithelial (MTE) cells
Observational studies show an association between statin use and improved lung health in asthma and chronic obstructive pulmonary disease (COPD), e.g. reduced decline in Forced expiratory volume in the first second (FEV1) and Forced vital capacity (FVC), reduced exacerbations, and reduced mortality in COPD [3,4,5,6,7] Several small clinical trials using statins to treat asthma have shown an anti-inflammatory effect as measured by reduced sputum leukotriene levels and leukocyte cell counts such as macrophages and eosinophils [8,9,10]

Summary

Introduction

Asthma is a leading cause of morbidity worldwide affecting children and adults alike. The statins are widely-used cholesterol-lowering drugs that have revolutionized the treatment of cardiovascular diseases. The statins have pleiotropic HMGR- or MA-independent effects beyond lowering cholesterol that, at least in part, belie their immunomodulatory and anti-inflammatory properties [1,2]. Observational studies show an association between statin use and improved lung health in asthma and chronic obstructive pulmonary disease (COPD), e.g. reduced decline in FEV1 and FVC, reduced exacerbations, and reduced mortality in COPD [3,4,5,6,7] Several small clinical trials using statins to treat asthma have shown an anti-inflammatory effect as measured by reduced sputum leukotriene levels and leukocyte cell counts such as macrophages and eosinophils [8,9,10]. The statin drugs, which treat hyperlipidemia and cardiovascular diseases, have pleiotropic effects beyond lowering cholesterol, including immunomodulatory, anti-inflammatory, and anti-fibrotic properties which may benefit lung health. Using an allergic mouse model of asthma, we previously demonstrated a benefit of statins in reducing peribronchiolar eosinophilic inflammation, airway hyperreactivity, goblet cell hyperplasia, and lung IL-4 and IL-13 production

Objectives

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Results

Conclusion