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Activation of Toll-Like Receptor 3 Augments Myofibroblast Differentiation

¹ Third Department of Internal Medicine, Wakayama Medical University School of Medicine, Wakayama, Japan

Correspondence and requests for reprints should be addressed to Masakazu Ichinose, M.D., Ph.D., Third Department of Internal Medicine, Wakayama Medical University School of Medicine, 811-1 Kimiidera, Wakayama, Wakayama 641-0012, Japan. E-mail: masakazu{at}wakayama-med.ac.jp

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 -smooth muscle actin (-SMA), a marker of myofibroblast differentiation, was evaluated. The release of transforming growth factor-β₁ (TGF-β₁) and ECM protein production were assessed. The effect of anti-TGF-β antibody on the -SMA and ECM production was also assessed. Poly(I:C) significantly augmented the -SMA expression (P < 0.01) and release of TGF-β₁ (P < 0.01) compared with control. Bafilomycin, an inhibitor of TLR3 signaling, diminished poly(I:C)-augmented TGF-β₁ release. Anti–TGF-β₁ antibody inhibited the poly(I:C)-augmented -SMA expression. Poly(I:C) enhanced translocation of nuclear factor-kB (NF-B) and interferon regulatory factor-3 (IRF-3) into the nucleus. Poly(I:C)-augmented TGF-β₁ release was almost completely blocked by NF-B 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-β antibody. These results suggest that activation of TLR3 can affect the differentiation to myofibroblasts and enhance ECM production via the NF-B–TGF-β₁–dependent pathway.

Key Words: viral infection • transforming growth factor-β₁ • nuclear factor-kappa B • airway remodeling • asthma

CLINICAL RELEVANCE Activation of Toll-like receptor 3 by double-stranded RNA can affect the differentiation to myofibroblasts and enhanced extracellular matrix production that are related to the airway remodeling after viral-induced exacerbations in asthma via the NF-B–TGF-β1–dependent pathway.