Premium
Regulation of procollagen I (α1) by interleukin‐4 in human bronchial fibroblasts: a possible role in airway remodelling in asthma
Author(s) -
Bergeron C.,
Pagé N.,
Joubert P.,
Barbeau B.,
Hamid Q.,
Chakir J.
Publication year - 2003
Publication title -
clinical and experimental allergy
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.462
H-Index - 154
eISSN - 1365-2222
pISSN - 0954-7894
DOI - 10.1046/j.1365-2222.2003.01785.x
Subject(s) - procollagen peptidase , stimulation , gene expression , endocrinology , chemistry , fibroblast , messenger rna , beta 2 microglobulin , medicine , interleukin 8 , immunology , microbiology and biotechnology , biology , gene , cytokine , in vitro , biochemistry
Summary Background In bronchial mucosa, T cells are in close association with fibroblasts. This cell contact raises the possibility of cross‐talk between the two cell types through cytokines, such as interleukin‐4 (IL‐4). Objective We postulated that IL‐4 may modulate collagen synthesis and degradation in the fibroblasts of asthmatics. Methods Bronchial fibroblasts from asthmatics (BAF) and normal controls (BNF) were stimulated with IL‐4. Procollagen I gene expression and protein production were measured by real‐time PCR, RT‐PCR, and radioimmunoassay. The effect of IL‐4 on the regulation of procollagen I (α 1 ) promoter was studied through transient cell transfections. The implication of Sp1 and AP‐1 in regulating IL‐4‐induced procollagen I (α 1 ) production was determined. The effect of IL‐4 on metalloproteinase‐2 (MMP‐2) and tissue inhibitor of metalloproteinase‐2 (TIMP‐2) production and gene expression was evaluated. Results Following IL‐4 stimulation, there was a significant increase in the expression of mRNA of procollagen I (α 1 ) by human bronchial fibroblasts of asthmatics and controls. IL‐4 has a dose–response effect on mRNA, with a maximal effect at 5 ng/mL, as determined by real‐time PCR. The maximal increase in procollagen I (α 1 ) was observed at 6 h after IL‐4 stimulation in both BNF and BAF. BAFs have a greater increase in the procollagen I (α 1 )/β 2 microglobulin ratio after 6 h of IL‐4 stimulation (4.1×10 −2 ±0.03 to 20.8×10 −2 ±0.1) compared with BNF (2.9×10 −2 ±0.006 to 9.2×10 −2 ±0.08) ( P =0.001). In transient transfection experiments, IL‐4 increased promoter activity by threefold in BAF and BNF. Sp1 was up‐regulated after IL‐4 stimulation and AP‐1 was down‐regulated as shown by electrophoretic mobility shift assay. IL‐4 decreased MMP‐2 protein and mRNA levels, and did not alter TIMP‐2 production. Conclusions IL‐4 positively regulates procollagen I (α 1 ) transcription by direct promoter activation and increases the TIMP‐2/MMP‐2 ratio, thereby supporting the profibrotic effect of this cytokine. Thus, this study emphasizes that IL‐4 may be considered as a link between inflammation and collagen deposition observed in asthmatic airways.