A promoter SNP rs4073T>A in the common allele of the interleukin 8 gene is associated with the development of idiopathic pulmonary fibrosis via the IL-8 protein enhancing mode

Abstract

BackgroundInterleukin-8 (IL-8) is a potent chemo-attractant cytokine responsible for neutrophil infiltration in lungs with idiopathic pulmonary fibrosis (IPF). The IL-8 protein and mRNA expression are increased in the lung with IPF. We evaluated the effect of single nucleotide polymorphisms (SNPs) of the IL-8 gene on the risk of IPF.MethodsOne promoter (rs4073T>A) and two intronic SNPs (rs2227307T>G and rs2227306C>T) of the IL-8 genes were genotyped in 237 subjects with IPF and 456 normal controls. Logistic regression analysis was applied to evaluate the association of these SNPs with IPF. IL-8 in BAL fluids was measured using a quantitative sandwich enzyme immunoassay, and promoter activity was assessed using the luciferase reporter assay.ResultsThe minor allele frequencies of rs4073T>A and rs2227307T>G were significantly lower in the 162 subjects with surgical biopsy-proven IPF and 75 subjects with clinical IPF compared with normal controls in the recessive model (OR = 0.46 and 0.48, p = 0.006 and 0.007, respectively). The IL-8 protein concentration in BAL fluids significantly increased in 24 subjects with IPF compared with 14 controls (p = 0.009). Nine IPF subjects homozygous for the rs4073 T>A common allele exhibited higher levels of the IL-8 protein compared with six subjects homozygous for the minor allele (p = 0.024). The luciferase activity of the rs4073T>A common allele was significantly higher than that of the rs4073T>A minor allele (p = 0.002).ConclusionThe common allele of a promoter SNP, rs4073T>A, may increase susceptibility to the development of IPF via up-regulation of IL-8.

Transient Receptor Potential Channels as Drug Targets: From the Science of Basic Research to the Art of Medicine

“…Interestingly, increased IL-8 levels were also found in the BAL of patients with IPF (Willems et al, 2013), and polymorphism in the IL-8 gene has been linked to IPF (Ahn et al, 2011). It was recently speculated that COPD and IPF may be "distinct horns of the same devil" (Chilosi et al, 2012).…”

Evaluation of chemokines CXCL8 and CCL2, serotonin, and vascular endothelial growth factor serum concentrations in healthy dogs from seven breeds with variable predisposition for canine idiopathic pulmonary fibrosis

“…Nevertheless, some studies highlighted the fact that IPF patients with a high TGF-β1 producing genotype are incline to have a worse prognosis and a more rapid deterioration in lung function (Arkwright et al, 2000;Alhamad et al, 2013). A single nucleotide polymorphism (rs4073T N A) was also recently found in the promoter of the CXCL8 gene and was significantly associated with higher BALF CXCL8 concentrations and an increased risk of development of IPF in humans (Ahn et al, 2011). Existence of such polymorphism in CIPF dogs has not yet been investigated.…”

“…Therefore, the aim of the present study was to compare basal circulating blood concentrations of four molecules of interest obtained in healthy dogs from seven breeds differently predisposed to CIPF. Selection of molecules studied was based on their potential implication into the pathogenesis of canine pulmonary fibrosis in view of data from either human or canine literature and were as follows: the chemokine (C-X-C motif) ligand 8 (CXCL8) (Cui et al, 2010;Ahn et al, 2011;Krafft et al, 2013), the chemokine (C-C motif) ligand 2 (CCL2) Moore, 2014), the serotonin (5-HT) (Konigshoff et al, 2010;Krafft et al, 2013), and the vascular endothelial growth factor (VEGF) (Ando et al, 2010;Woodcock et al, 2013).…”

Analysis of polymorphisms of genes associated with immune response and tissue remodeling in occupational chronic bronchitis

“…In addition, increased IL8 con centrations in bronchoalveolar lavage correlated with decreased FEV1 values [8]. The IL8 (-251T>A) variant was also associated with an increased risk of idiopathic lung fibrosis [38]. A study from China showed that IL8 variants can contribute significantly to COPD risk in residents of regions with high air pollution levels [39].…”