TLR3 activation augments matrix metalloproteinase production through reactive nitrogen species generation in human lung fibroblasts

Tomohiro Ichikawa, Hisatoshi Sugiura, Akira Koarai, Yoshiaki Minakata, Takashi Kikuchi, Yukiko Morishita, Asako Oka, Kuninobu Kanai, Hiroki Kawabata, Masataka Hiramatsu, Keiichiro Akamatsu, Tsunahiko Hirano, Masanori Nakanishi, Kazuto Matsunaga, Nobuyuki Yamamoto, Masakazu Ichinose

Research output: Contribution to journalArticlepeer-review

21 Citations (Scopus)

Abstract

Viral infection often triggers asthma exacerbation and contributes to airway remodeling. Cell signaling in viral infection is mainly mediated through TLR3. Many mediators are involved in airway remodeling, but matrix metalloproteinases (MMPs) are key players in this process in asthma. However, the role of TLR3 activation in production of MMPs is unknown. In this study, we examined the effects of polyinosinic-polycytidylic acid [poly(I:C)], a ligand for TLR3, on production of MMPs in human lung fibroblasts, with a focus on nitrosative stress in TLR3 modulation of MMP production. After lung fibroblasts were treated with poly(I:C), production of MMP-1, -2, and -9 and inducible NO synthase (iNOS) was assessed. The roles of NF-κB and IFN regulatory factor-3 (IRF-3) in the poly(I:C)-mediated production of MMPs and the responsiveness to poly(I:C) of normal lung fibroblasts and asthmatic lung fibroblasts were also investigated. Poly(I:C) augmented production of MMPs and iNOS in fibroblasts, and an iNOS inhibitor diminished this production of MMPs. Poly(I:C) stimulated translocation of NF-κB and IRF-3 into the nucleus in fibroblasts and inhibition of NF-κB or IRF-3 abrogated the poly(I:C)-induced increase in both iNOS expression and release of MMPs. Poly(I:C)-induced production of iNOS and MMPs was greater in asthmatic fibroblasts than in normal fibroblasts. We conclude that viral infection may induce nitrosative stress and subsequent MMP production via NF-κB- and IRF-3-dependent pathways, thus potentiating viral-induced airway remodeling in asthmatic airways.

Original languageEnglish
Pages (from-to)4977-4988
Number of pages12
JournalJournal of Immunology
Volume192
Issue number11
DOIs
Publication statusPublished - 2014 Jun 1

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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