Activation of Toll-like receptor 3 augments myofibroblast differentiation.
Airway remodeling is observed in the airways of patients with asthma, and differentiation of fibroblasts to myofibroblasts plays a critical role in the progress of airway remodeling. Viral infection induces not only the disease development and exacerbations but also airway remodeling. The aim of this study was to evaluate whether the activation of Toll-like receptor 3 (TLR3) can affect the differentiation of fibroblasts to myofibroblasts and the extracellular matrix (ECM) protein production. Human fetal lung fibroblasts (HFL-1) and adult lung fibroblasts were treated with a synthetic double-stranded RNA, polyinosine-polycytidylic acid (poly[I:C]) and the expression of alpha-smooth muscle actin (alpha-SMA), a marker of myofibroblast differentiation, was evaluated. The release of transforming growth factor-beta(1) (TGF-beta(1)) and ECM protein production were assessed. The effect of anti-TGF-beta antibody on the alpha-SMA and ECM production was also assessed. Poly(I:C) significantly augmented the alpha-SMA expression (P < 0.01) and release of TGF-beta(1) (P < 0.01) compared with control. Bafilomycin, an inhibitor of TLR3 signaling, diminished poly(I:C)-augmented TGF-beta(1) release. Anti-TGF-beta(1) antibody inhibited the poly(I:C)-augmented alpha-SMA expression. Poly(I:C) enhanced translocation of nuclear factor-kB (NF-kappaB) and interferon regulatory factor-3 (IRF-3) into the nucleus. Poly(I:C)-augmented TGF-beta(1) release was almost completely blocked by NF-kappaB inhibitors, but not by silencing IRF-3. The production of fibronectin and collagen I expression were significantly increased by poly(I:C) (P < 0.01) and they were inhibited by anti-TGF-beta antibody. These results suggest that activation of TLR3 can affect the differentiation to myofibroblasts and enhance ECM production via the NF-kappaB-TGF-beta(1)-dependent pathway.
Sugiura
Hisatoshi
H
Third Department of Internal Medicine, Wakayama Medical University School of Medicine, Wakayama, Wakayama, Japan.
Ichikawa
Tomohiro
T
Koarai
Akira
A
Yanagisawa
Satoru
S
Minakata
Yoshiaki
Y
Matsunaga
Kazuto
K
Hirano
Tsunahiko
T
Akamatsu
Keiichiro
K
Ichinose
Masakazu
M
D001249:Asthma / Q000378:metabolism; D002454:Cell Differentiation; D003094:Collagen / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism*; D005353:Fibronectins / Q000378:metabolism; D020868:Gene Silencing; D006801:Humans; D008856:Microscopy, Fluorescence; D008954:Models, Biological; D009132:Muscles / Q000378:metabolism / Q000473:pathology; D016328:NF-kappa B / Q000378:metabolism; D011070:Poly I-C / Q000494:pharmacology; D015398:Signal Transduction; D051196:Toll-Like Receptor 3 / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism
D005353:Fibronectins; D016328:NF-kappa B; D051196:Toll-Like Receptor 3; D016212:Transforming Growth Factor beta; D003094:Collagen; D011070:Poly I-C