Analysis on the Relevance of Asthma Susceptibility with the Alteration of Integrin β 4 Expression

Abstract

Accumulated research has suggested the importance of the adhesion molecules modulation as therapeutic approach for bronchial asthma. Adhesion molecules expression alteration contributes to the pathogenesis of asthma. In order to probe the roles of expression imbalance of adhesion molecules in asthma pathogenesis, expression profiling of adhesion molecules was performed using cDNA microarray assay. The results showed that the expression pattern of adhesion molecules was altered in peripheral blood leucocytes of asthma patients. In this study, we focused on one of the abnormally expressed molecule, integrin β4, which was down-regulated in all asthma patients, to analyze the relevance of asthma susceptibility with the alteration of integrin β4 expressions. Real time PCR was used to verify the down-regulation of integrin β4 in additional 38 asthma patients. Next, the 5′flanking region of integrin β4 DNA were amplified, sequenced and site-directed mutagenesis technology in correspondent variation sites were carried out. Among 4 variation sites found in 5′ flanking region of integrin β4, 3 were related to asthma susceptibility: -nt1029 G/A, -nt 1051 G/A, and -nt 1164 G/C. A reduction of human integrin β4 promoter activity was observed at mutants of these sites. This study demonstrates that various adhesion molecules in asthma patients are abnormally expressed. Mutations in 5′ flanking region result in reduced integrin β4 expression, which is related to increased risk of asthma.

ITGB4is essential for containing HDM-induced airway inflammation and airway hyperresponsiveness

“…By cDNA microarray assay, our previous work demonstrated that ITGB4 is downregulated in asthma airway epithelial cells with 4 variation sites in 5′ flanking region . ITGB4 is a traditional adhesion molecule that mediates the anchoring of airway epithelial cells to the basal membrane.…”

“…As the airway epithelium is the first cellular barrier to external allergens, structural damage, and loss of function in these cells could alter airway inflammation reactions after allergic stress. Our previous work demonstrated that structural adhesion molecule integrin β4 (ITGB4) is downregulated in asthma airway epithelial cells with 4 variation sites in 5′ flanking region . ITGB4 is located at the basal surface of airway epithelial cells in hemidesmosomal structures that mediate the stable adhesion of epidermal cells to the underlying basement membrane component laminin‐5 .…”

INTEGRIN BETA 4 mRNA EXPRESSION LEVELS IN BRONCHIAL ASTHMA PATIENTS

“…Liu et al 2010 Provided evidences that ITGβ4 was involved in the structural integrity and functional homeostasis of airway epithelial cells (Liu et al, 2010b). The results of Zhou et al, 2008 andXiang et al, 2014, showed that the expressions of integrin β4 were down-regulated in asthma patients, and that it was associated with the variation in5'flanking region.…”

“…Moreover, Sheppard 2003 showed that integrinβ4 expression was clearly elevated after airway epithelialinjuryand could be detected in many cell types, which suggest that integrin β4 might be involved in the repair processes of airway epithelium (Sheppard 2003). Xiang et al, 2014 found thatmutations in 5̄ flanking region of integrin β4 gene result in reduced integrin β4 expression, and that it was related to increased risk of asthma (Xiang et al, 2014). ITGs are heterodimeric receptors that mediate cell adhesion, migration and tissue organization (Staunton et al, 2006) and might be a death factor in endothelial cells (Hiran et al, 2003).…”

Airway epithelial ITGB4 deficiency in early life mediates pulmonary spontaneous inflammation and enhanced allergic immune response

“…Integrins play important roles in the adhesion, tissue repair and microenvironment homeostasis of airway epithelial cells . Among these molecules, ITGB4 has been shown to decrease significantly in the airway epithelial cells of asthma patients with specific variant sites . By binding with basement membrane component laminin‐5, ITGB4 mediates the structural adhesion of airway epithelial cells to basal surface in hemi‐desmosome structure .…”