Interleukin-13 Induces Airway Fibroblast Invasion In Asthma: Implications For A Mechanism Dependent On MMPs And TGF-beta

Ingram, Jennifer L.; Huggins, Molly J.; Church, Tony D.; Francisco, Dave; Firszt, Rafael; Degan, Simone; Noble, Paul W.; Beaver, Denise; Sunday, Mary E.; Kraft, Monica

doi:10.1164/ajrccm-conference.2010.181.1_meetingabstracts.a1072

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“…We demonstrated that IL-13Ra2 expression in airway fibroblasts from subjects with asthma was suppressed compared with that of normal patients. Some of the results of these studies have been reported previously in the form of abstracts (18,19).…”

Section: What This Study Adds To the Fieldmentioning

confidence: 89%

Airway Fibroblasts in Asthma Manifest an Invasive Phenotype

Ingram

Huggins

Church

et al. 2011

Am J Respir Crit Care Med

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Rationale: Invasive cell phenotypes have been demonstrated in malignant transformation, but not in other diseases, such as asthma. Cellular invasiveness is thought to be mediated by transforming growth factor (TGF)-b1 and matrix metalloproteinases (MMPs). IL-13 is a key T H 2 cytokine that directs many features of airway remodeling through TGF-b1 and MMPs. Objectives: We hypothesized that, in human asthma, IL-13 stimulates increased airway fibroblast invasiveness via TGF-b1 and MMPs in asthma compared with normal controls. Methods: Fibroblasts were cultured from endobronchial biopsies in 20 subjects with mild asthma (FEV 1 : 90 6 3.6% pred) and 17 normal control subjects (FEV 1 : 102 6 2.9% pred) who underwent bronchoscopy. Airway fibroblast invasiveness was investigated using Matrigel chambers. IL-13 or IL-13 with TGF-b1 neutralizing antibody or pan-MMP inhibitor (GM6001) was added to the lower chamber as a chemoattractant. Flow cytometry and immunohistochemistry were performed in a subset of subjects to evaluate IL-13 receptor levels. Measurements and Main Results: IL-13 significantly stimulated invasion in asthmatic airway fibroblasts, compared with normal control subjects. Inhibitors of both TGF-b1 and MMPs blocked IL-13-induced invasion in asthma, but had no effect in normal control subjects. At baseline, in airway tissue, IL-13 receptors were expressed in significantly higher levels in asthma, compared with normal control subjects. In airway fibroblasts, baseline IL-13Ra2 was reduced in asthma compared with normal control subjects. Conclusions: IL-13 potentiates airway fibroblast invasion through a mechanism involving TGF-b1 and MMPs. IL-13 receptor subunits are differentially expressed in asthma. These effects may result in IL-13-directed airway remodeling in asthma.

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Section: What This Study Adds To the Fieldmentioning

confidence: 89%