title: Extracellular 14-3-3 from human lung epithelial cells enhances MMP-1 expression.
abstract: Airway remodelling in asthma involves various mediators modulating the production/breakdown of collagen by lung fibroblasts. Matrix metalloproteinase-1 (MMP-1) plays an important role in collagen breakdown. We recently showed that epithelial cell-derived extracellular form of 14-3-3σ is an important inducer of MMP-1 expression in skin fibroblasts. Thus, we hypothesized that 14-3-3 proteins are important regulators of MMP-1 expression in the respiratory airway. We examined the presence of extracellular 14-3-3 proteins in conditioned media obtained from primary lung epithelial cells, A549 and HS24 cells, and their effect on MMP-1 expression by lung fibroblasts (IMR-90). In addition, we evaluated IMR-90 response to 14-3-3 proteins in the presence of transforming growth factor-β(1) (TGF-β(1)), a cytokine known to decrease MMP-1 expression by fibroblasts. Extracellular 14-3-3α/β, but not -σ, is released by the human-derived lung epithelial cell lines, A549 and HS24. Unlike dermal fibroblasts, IMR-90 cells do not produce MMP-1 in response to 14-3-3σ. Conversely, MMP-1 production was induced following treatment of IMR-90 with recombinant or lung epithelial cell-derived 14-3-3α/β. These findings were also confirmed using primary human bronchial epithelial cells and lung fibroblasts obtained from non-asthmatic patients. The MMP-1-inducing effect of 14-3-3α/β on IMR-90 was not inhibited by TGF-β(1). Lung epithelial cell-derived 14-3-3α/β has a potent MMP-1-inducing effect on airway fibroblasts. Modulation of MMP-1 by 14-3-3α/β, may be important in the alteration of collagenase production associated with airway remodelling in obstructive lung diseases. Our data indicate that 14-3-3 proteins may be potential targets for future therapeutic strategies aimed at modulating tissue remodelling in asthma.
authors.affiliation: Department of Medicine, Pulmonary Research Group, University of Alberta, Edmonton, AB, Canada.
authors.forename: Negar
authors.initials: N
authors.lastname: Asdaghi
authors.forename: Ruhangiz T
authors.initials: RT
authors.lastname: Kilani
authors.forename: Azadeh
authors.initials: A
authors.lastname: Hosseini-Tabatabaei
authors.forename: Solomon O
authors.initials: SO
authors.lastname: Odemuyiwa
authors.forename: Tillie-Louise
authors.initials: TL
authors.lastname: Hackett
authors.forename: Darryl A
authors.initials: DA
authors.lastname: Knight
authors.forename: Aziz
authors.initials: A
authors.lastname: Ghahary
authors.forename: Redwan
authors.initials: R
authors.lastname: Moqbel
mesh_terms: D048948:14-3-3 Proteins / Q000378:metabolism / Q000502:physiology*; D056151:Airway Remodeling; D014408:Biomarkers, Tumor / Q000378:metabolism; D045744:Cell Line, Tumor; D017077:Culture Media, Conditioned; D004847:Epithelial Cells / Q000201:enzymology / Q000378:metabolism*; D005092:Exonucleases / Q000378:metabolism; D005095:Exoribonucleases; D005347:Fibroblasts / Q000201:enzymology / Q000378:metabolism; D015870:Gene Expression; D005786:Gene Expression Regulation; D006801:Humans; D007249:Inflammation; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008168:Lung / Q000473:pathology*; D020781:Matrix Metalloproteinase 1 / Q000235:genetics / Q000378:metabolism*; D061251:Primary Cell Culture; D020033:Protein Isoforms / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology / Q000502:physiology
chemical_list: D048948:14-3-3 Proteins; D014408:Biomarkers, Tumor; D017077:Culture Media, Conditioned; D020033:Protein Isoforms; D053773:Transforming Growth Factor beta1; C482982:YWHAB protein, human; D007770:L-Lactate Dehydrogenase; D005092:Exonucleases; D005095:Exoribonucleases; C413442:SFN protein, human; C522360:MMP1 protein, human; D020781:Matrix Metalloproteinase 1