3) Disease development in IPF is thought to result

3). Disease development in IPF is thought to result selleck kinase inhibitor from repetitive injury to epithelial cells and an abnormal fibrotic response. Proinflammatory mediators, such as IL-1β, are known to promote fibrosis, but can be regulated by the receptor antagonist IL-1Ra. In the present study, we found that the ratio between IL-1Ra and IL-1β was decreased in both serum and BALF of IPF patients compared to healthy controls. Furthermore, we showed that one SNP in IL1RN, rs2637988, associated with susceptibility

to IPF and with the IL-1Ra/IL-1β ratio in BALF. A predisposing effect of genetic variation in IL1RN was described previously by Whyte et al., who found an increased risk of fibrosing alveolitis in an Italian and a British population [6]. They investigated the IL1RN + 2018 SNP, which in the Caucasian Hapmap panel is in complete linkage Cell Cycle inhibitor disequilibrium with our tag rs408392 (r2 = 1). In our study, rs408392 was not the most significantly associated SNP, although carriership of allele 2 of rs408392 was more common in patients with IPF (P = 0·07). In other studies the variable number of tandem repeats (VNTR) in intron 2 of IL1RN was investigated and found to be in linkage disequilibrium with the IL1RN + 2018 SNP. However, both a small Australian [7] and an independent Czech cohort [12] did not reveal any association between the VNTR and

IPF susceptibility [13]. Functional effects of IL1RN + 2018 alleles have been demonstrated by Carter et al. They showed that IL1RN + 2018 allele 2 not only correlated with Racecadotril the susceptibility to ulcerative colitis, but also to a significantly decreased ratio between the protein and mRNA content of IL-1Ra and total IL-1 in the colonic mucosa [14]. Although we found the same trend as reported in the Italian and British cohorts, our data suggest that carriership

of the G allele of IL1RN rs2637988 is associated more strongly with IPF. Carriership of the G-allele is higher in IPF patients (75%) compared to controls (61%), P = 0·02. In addition, we showed that IPF patients carrying the rs2637988 G-allele had a significantly lower IL-1Ra/IL-1β ratio in BALF, suggesting a relative shortage of IL-1Ra compared to IL-1β. This implies that presence of the G allele has a pathogenic role in IPF. The balance between IL-1 and IL-1Ra seems crucial in inflammatory diseases [15–18]. Although IPF is not primarily an inflammatory disease, IPF is characterized by high levels of inflammatory parameters. The balance between IL-1 and IL-1Ra has rarely been studied in IPF, but extensively in inflammatory diseases. In inflammatory bowel disease, changes in the IL-1Ra/IL-1β ratio have also been studied. Protein levels in the colonic mucosa of IL-1Ra, IL-1α and IL-1β were higher than in controls, but the ratio between IL-1Ra and total IL-1 was decreased significantly [14,19].

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