Interleukin 13 exposure enhances vitamin D-mediated expression of the human cathelicidin antimicrobial peptide 18/LL-37 in bronchial epithelial cells.

Vitamin D is an important regulator of the expression of antimicrobial peptides, and vitamin D deficiency is associated with respiratory infections. Regulating expression of antimicrobial peptides, such as the human cathelicidin antimicrobial peptide 18 (hCAP18)/LL-37, by vitamin D in bronchial epithelial cells requires local conversion of 25(OH)-vitamin D(3) (25D(3)) into its bioactive metabolite, 1,25(OH)(2)-vitamin D(3) (1,25D(3)), by CYP27B1. Low circulating vitamin D levels in childhood asthma are associated with more-severe exacerbations, which are often associated with infections. Atopic asthma is accompanied by Th2-driven inflammation mediated by cytokines such as interleukin 4 (IL-4) and IL-13, and the effect of these cytokines on vitamin D metabolism and hCAP18/LL-37 expression is unknown. Therefore, we investigated this with well-differentiated bronchial epithelial cells. To this end, cells were treated with IL-13 with and without 25D(3), and expression of hCAP18/LL-37, CYP27B1, the 1,25D(3)-inactivating enzyme CYP24A1, and vitamin D receptor was assessed by quantitative PCR. We show that IL-13 enhances the ability of 25D(3) to increase expression of hCAP18/LL-37 and CYP24A1. In addition, exposure to IL-13 resulted in increased CYP27B1 expression, whereas vitamin D receptor (VDR) expression was not significantly affected. The enhancing effect of IL-13 on 25D(3)-mediated expression of hCAP18/LL-37 was further confirmed using SDS-PAGE Western blotting and immunofluorescence staining. In conclusion, we demonstrate that IL-13 induces vitamin D-dependent hCAP18/LL-37 expression, most likely by increasing CYP27B1. These data suggest that Th2 cytokines regulate the vitamin D metabolic pathway in bronchial epithelial cells.

Bronchial matrix and inflammation respond to inhaled steroids despite ongoing allergen exposure in asthma.

BACKGROUND: Inflammatory and structural changes of the airway mucosa are chronic features of asthma. The mechanisms underlying these changes and their modulation by steroid prophylaxis have not been clarified. OBJECTIVE: We postulated that asymptomatic ongoing allergen exposure could drive airway inflammation as well as changes in the extracellular matrix (ECM), and that inhaled steroids could prevent this. METHODS: Therefore, we exposed patients with mild asthma to 2 weeks of repeated low-dose allergen, with concomitant inhaled steroid or placebo treatment. Bronchial biopsies, which were taken before and after this exposure, were stained and digitally analysed. The ECM proteins in asthmatics were also compared with a normal control group. RESULTS: Low-dose allergen exposure alone resulted in a significant increase of bronchial epithelial macrophages. Despite ongoing allergen exposure, inhaled steroids reduced the numbers of mucosal eosinophils, neutrophils and T lymphocytes. At baseline, the mean density of the proteoglycans (PGS) biglycan and decorin were, respectively, higher and lower in the bronchial mucosa of asthmatics as compared with normal controls. Steroid treatment, during allergen exposure, increased the mean density of the PGS biglycan and versican. CONCLUSION: We conclude that chronic allergen exposure induces inflammatory changes in the bronchial mucosa. Despite ongoing allergen exposure, steroid treatment decreases mucosal inflammatory cells while altering PG density. The latter observation highlights the need to examine steroid-induced changes closely in the airway structure in patients with asthma.