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10.1074/jbc.M114.582262

http://scihub22266oqcxt.onion/10.1074/jbc.M114.582262
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suck abstract from ncbi


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pmid25339175
      J+Biol+Chem 2014 ; 289 (51 ): 35246-63
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  • Influenza promotes collagen deposition via ?v?6 integrin-mediated transforming growth factor ? activation #MMPMID25339175
  • Jolly L ; Stavrou A ; Vanderstoken G ; Meliopoulos VA ; Habgood A ; Tatler AL ; Porte J ; Knox A ; Weinreb P ; Violette S ; Hussell T ; Kolb M ; Stampfli MR ; Schultz-Cherry S ; Jenkins G
  • J Biol Chem 2014[Dec]; 289 (51 ): 35246-63 PMID25339175 show ga
  • Influenza infection exacerbates chronic pulmonary diseases, including idiopathic pulmonary fibrosis. A central pathway in the pathogenesis of idiopathic pulmonary fibrosis is epithelial injury leading to activation of transforming growth factor ? (TGF?). The mechanism and functional consequences of influenza-induced activation of epithelial TGF? are unclear. Influenza stimulates toll-like receptor 3 (TLR3), which can increase RhoA activity, a key event prior to activation of TGF? by the ?v?6 integrin. We hypothesized that influenza would stimulate TLR3 leading to activation of latent TGF? via ?v?6 integrin in epithelial cells. Using H1152 (IC50 6.1 ?m) to inhibit Rho kinase and 6.3G9 to inhibit ?v?6 integrins, we demonstrate their involvement in influenza (A/PR/8/34 H1N1) and poly(I:C)-induced TGF? activation. We confirm the involvement of TLR3 in this process using chloroquine (IC50 11.9 ?m) and a dominant negative TLR3 construct (pZERO-hTLR3). Examination of lungs from influenza-infected mice revealed augmented levels of collagen deposition, phosphorylated Smad2/3, ?v?6 integrin, and apoptotic cells. Finally, we demonstrate that ?v?6 integrin-mediated TGF? activity following influenza infection promotes epithelial cell death in vitro and enhanced collagen deposition in vivo and that this response is diminished in Smad3 knock-out mice. These data show that H1N1 and poly(I:C) can induce ?v?6 integrin-dependent TGF? 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.
  • |1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine/analogs & derivatives/pharmacology [MESH]
  • |Animals [MESH]
  • |Antigens, Neoplasm/genetics/*metabolism [MESH]
  • |Antiviral Agents/pharmacology [MESH]
  • |Apoptosis [MESH]
  • |Cell Line, Transformed [MESH]
  • |Collagen/*metabolism [MESH]
  • |Dogs [MESH]
  • |Epithelial Cells/drug effects/*metabolism/virology [MESH]
  • |Host-Pathogen Interactions [MESH]
  • |Humans [MESH]
  • |Immunoblotting [MESH]
  • |Influenza A Virus, H1N1 Subtype/physiology [MESH]
  • |Integrins/genetics/*metabolism [MESH]
  • |Lung/metabolism/virology [MESH]
  • |Madin Darby Canine Kidney Cells [MESH]
  • |Mice, Inbred C57BL [MESH]
  • |Mice, Knockout [MESH]
  • |Orthomyxoviridae Infections/genetics/*metabolism/virology [MESH]
  • |Phosphorylation/drug effects [MESH]
  • |Poly I-C/pharmacology [MESH]
  • |Smad3 Protein/genetics/metabolism [MESH]
  • |Toll-Like Receptor 3/metabolism [MESH]
  • |Transforming Growth Factor beta/genetics/*metabolism [MESH]


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