title: Interleukin-13 induces collagen type-1 expression through matrix metalloproteinase-2 and transforming growth factor-β1 in airway fibroblasts in asthma.
abstract: Airway remodelling is a feature of asthma that contributes to loss of lung function. One of the central components of airway remodelling is subepithelial fibrosis. Interleukin (IL)-13 is a key T-helper 2 cytokine and is believed to be the central mediator of allergic asthma including remodelling, but the mechanism driving the latter has not been elucidated in human asthma. We hypothesised that IL-13 stimulates collagen type-1 production by the airway fibroblast in a matrix metalloproteinase (MMP)- and transforming growth factor (TGF)-β1-dependent manner in human asthma as compared to healthy controls. Fibroblasts were cultured from endobronchial biopsies in 14 subjects with mild asthma and 13 normal controls that underwent bronchoscopy. Airway fibroblasts were treated with various mediators including IL-13 and specific MMP-inhibitors. IL-13 significantly stimulated collagen type-1 production in asthma compared to normal controls. Inhibitors of MMP-2 significantly attenuated collagen production in asthma but had no effect in normal controls. IL-13 significantly increased total and active forms of TGF-β1, and this activation was blocked using an MMP-2 inhibitor. IL-13 activated endogenous MMP-2 in asthma patients as compared to normal controls. In an ex vivo model, IL-13 potentiates airway remodelling through a mechanism involving TGF-β1 and MMP-2. These effects provide insights into the mechanism involved in IL-13-directed airway remodelling in asthma.
authors.affiliation: Division of Allergy, Immunology and Rheumatology, University of Utah, Salt Lake City, UT.
authors.forename: Rafael
authors.initials: R
authors.lastname: Firszt
authors.forename: Dave
authors.initials: D
authors.lastname: Francisco
authors.forename: Tony D
authors.initials: TD
authors.lastname: Church
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Thomas
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Ingram
authors.forename: Monica
authors.initials: M
authors.lastname: Kraft
mesh_terms: D000199:Actins / Q000378:metabolism; D000328:Adult; D001249:Asthma / Q000378:metabolism*; D001706:Biopsy; D001980:Bronchi / Q000378:metabolism; D024042:Collagen Type I / Q000378:metabolism*; D016326:Extracellular Matrix Proteins / Q000378:metabolism*; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D018793:Interleukin-13 / Q000378:metabolism*; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D012129:Respiratory Function Tests; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D000099222:betaIG-H3 Protein
chemical_list: D000199:Actins; D024042:Collagen Type I; D016326:Extracellular Matrix Proteins; D018793:Interleukin-13; D020778:Matrix Metalloproteinase 2; D016212:Transforming Growth Factor beta; D000099222:betaIG-H3 Protein; C578095:IL13 protein, human; C522361:MMP2 protein, human