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.jpg): Failed to open stream: No such file or directory in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 117 J+Biol+Chem
2014 ; 289
(51
): 35246-63
Nephropedia Template TP
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.