Human β-defensin-3 Induces IL-8 Release and Apoptosis in Airway Smooth Muscle Cells

Abstract

Background

Human airway smooth muscle cells (ASMCs) may have a pro-inflammatory role through the release of inflammatory mediators. Increasing evidence indicates that human β-defensins (HBDs) are related to pathogenesis of asthma.

Objectives

To examine the plasma level of HBD-1, -2 and -3 in asthmatic patients and the expression of their mouse orthologs in the lung tissue of a mouse model of chronic severe asthma. Further to investigate the effect of HBD-3 on the release of the pro-inflammatory cytokine IL-8 and to explore the mechanisms.

Methods

The plasma levels of HBD-1, -2 and -3 from 34 healthy controls and 25 asthmatic patients were determined by ELISA. The expression of mouse β-defensins MBD-1, -3 and -14 in the lung tissue of asthmatic mice was detected by Western blot. The ASMCs were cultured with HBD-3 for 24h, and then the supernatant level of IL-8 was evaluated by ELISA and the cell viability was examined by WST-1 assay. The signaling pathway was investigated with blocking antibodies or pharmacological inhibitors.

Results

The plasma levels of HBD-1 and -3 were elevated in asthmatic patients, and the expression of MBD-14, the mouse ortholog for HBD-3, was increased in asthmatic mice. HBD-3 induced IL-8 production in a CCR6 receptor-specific manner and was dependent on multiple signaling pathways. Moreover, HBD-3 induced cell apoptosis concurrently, which was dependent on the ERK1/2 MAPK pathway. Mitochondrial ROS regulated both HBD-3-induced IL-8 production and cell apoptosis.

Conclusions & Clinical Relevance

These observations provide clear evidence of an important new mechanism for the promotion of airway inflammation and tissue remodeling with potential relevance for the treatment of asthma.

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