tetano
Editor, Senior Moderator
J Biol Chem. 2014 Oct 22. pii: jbc.M114.582262. [Epub ahead of print]
Influenza Promotes Collagen Deposition via αvβ6-integrin Mediated Transforming Growth Factor β Activation.
Jolly L1, Stavrou A1, Vanderstoken G2, Meliopoulos VA3, Habgood A1, Tatler AL1, Porte J1, Knox A1, Weinreb P4, Violette S4, Hussell T5, Kolb M2, Stampfli MR2, Schultz-Cherry S3, Jenkins G6.
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Abstract
Influenza infection exacerbates chronic pulmonary diseases including idiopathic pulmonary fibrosis (IPF). A central pathway in the pathogenesis of IPF is epithelial injury leading to activation of transforming growth factor β (TGFβ). The mechanism and functional consequences of influenza-induced activation of epithelial TGFβ are unclear. Influenza stimulates toll like receptor 3 (TLR3), which can increase RhoA activity, a key event prior to activation of TGFβ by the αvβ6-integrin. We hypothesized that influenza would stimulate TLR3 leading to activation of latent TGFβ via αvβ6-integrin in epithelial cells. Using H1152 (IC50 6.1 μM) to inhibit Rho kinase and 6.3G9 to inhibit αvβ6-integrin, we demonstrate their involvement in influenza (A/PR/8/34 H1N1) and poly(I:C) induced TGFβ activation. We confirm the involvement of TLR3 in this process using chloroquine (IC50 11.9 μM) and a dominant negative TLR3 construct (pZERO-hTLR3). Examination of lungs from influenza-infected mice revealed augmented levels of collagen deposition, phosphorylated Smad2/3, αvβ6-integrin and apoptotic cells. Finally, we demonstrate that αvβ6-integrin-mediated TGFβ activity following influenza infection promotes epithelial cell death in vitro and enhanced collagen deposition in vivo and that this response is diminished in Smad3 knockout mice. These data show that H1N1 and poly(I:C) can induce αvβ6-integrin dependent TGFβ activity in epithelial cells via stimulation of TLR3, and suggest a novel mechanism by which influenza infection may promote collagen deposition in fibrotic lung disease.
Copyright ? 2014, The American Society for Biochemistry and Molecular Biology.
KEYWORDS:
apoptosis; influenza; integrin; pulmonary fibrosis; toll-like receptor (TLR)
PMID:
25339175
[PubMed - as supplied by publisher]
Free full text
http://www.ncbi.nlm.nih.gov/pubmed/25339175
Influenza Promotes Collagen Deposition via αvβ6-integrin Mediated Transforming Growth Factor β Activation.
Jolly L1, Stavrou A1, Vanderstoken G2, Meliopoulos VA3, Habgood A1, Tatler AL1, Porte J1, Knox A1, Weinreb P4, Violette S4, Hussell T5, Kolb M2, Stampfli MR2, Schultz-Cherry S3, Jenkins G6.
Author information
Abstract
Influenza infection exacerbates chronic pulmonary diseases including idiopathic pulmonary fibrosis (IPF). A central pathway in the pathogenesis of IPF is epithelial injury leading to activation of transforming growth factor β (TGFβ). The mechanism and functional consequences of influenza-induced activation of epithelial TGFβ are unclear. Influenza stimulates toll like receptor 3 (TLR3), which can increase RhoA activity, a key event prior to activation of TGFβ by the αvβ6-integrin. We hypothesized that influenza would stimulate TLR3 leading to activation of latent TGFβ via αvβ6-integrin in epithelial cells. Using H1152 (IC50 6.1 μM) to inhibit Rho kinase and 6.3G9 to inhibit αvβ6-integrin, we demonstrate their involvement in influenza (A/PR/8/34 H1N1) and poly(I:C) induced TGFβ activation. We confirm the involvement of TLR3 in this process using chloroquine (IC50 11.9 μM) and a dominant negative TLR3 construct (pZERO-hTLR3). Examination of lungs from influenza-infected mice revealed augmented levels of collagen deposition, phosphorylated Smad2/3, αvβ6-integrin and apoptotic cells. Finally, we demonstrate that αvβ6-integrin-mediated TGFβ activity following influenza infection promotes epithelial cell death in vitro and enhanced collagen deposition in vivo and that this response is diminished in Smad3 knockout mice. These data show that H1N1 and poly(I:C) can induce αvβ6-integrin dependent TGFβ activity in epithelial cells via stimulation of TLR3, and suggest a novel mechanism by which influenza infection may promote collagen deposition in fibrotic lung disease.
Copyright ? 2014, The American Society for Biochemistry and Molecular Biology.
KEYWORDS:
apoptosis; influenza; integrin; pulmonary fibrosis; toll-like receptor (TLR)
PMID:
25339175
[PubMed - as supplied by publisher]
Free full text
http://www.ncbi.nlm.nih.gov/pubmed/25339175