Oxidative stress enhances toll-like receptor 3 response to double-stranded RNA in airway epithelial cells.

Abstract

Virus infections are a major cause of chronic obstructive pulmonary disease (COPD) exacerbations. Recently, Toll-like receptor 3 (TLR3) has been demonstrated to react to double-stranded RNA (dsRNA) and to be involved in the immune responses after viral infections. In the present study, we examined whether oxidative stress, which is involved in the pathogenesis of COPD, enhances the responses of TLR3 in airway epithelial cells. The effect of hydrogen peroxide (H(2)O(2)) on the release of IL-8 from BEAS-2B cells and primary human bronchial epithelial cells after stimulation with polyinosine-polycytidylic acid [poly(I:C)], a synthetic analog of viral dsRNA and a ligand for TLR3, and the signal transduction were examined. One hundred to 150 muM H(2)O(2) significantly potentiated the release of IL-8 from the epithelial cells after stimulation with 10 microg/ml poly(I:C). The H(2)O(2)-augmented IL-8 release was inhibited by treatment with N-acetylcysteine. One hundred micromoles of H(2)O(2) enhanced the translocation of nuclear factor (NF)-kappaB p65, but not that of interferon regulatory factor-3 (IRF-3), into the nucleus and the NF-kappaB DNA binding activity after poly(I:C) stimulation, which effect was inhibited not by the silencing of IRF-3 but by MG132, a proteasome inhibitor, or dexamethasone. One hundred micromoles of H(2)O(2) potentiated the TLR3 expression on the airway epithelial cells treated with poly(I:C). These data suggest that oxidative stress augments the response of TLR3 in airway epithelial cells via NF-kappaB and that this effect might be partly mediated by the enhancement of TLR3 expression. Modulation of this pathway may be a therapeutic target for viral-induced exacerbations of COPD.

• Authors: Akira Koarai, Hisatoshi Sugiura, Satoru Yanagisawa, Tomohiro Ichikawa, Yoshiaki Minakata, Kazuto Matsunaga, Tsunahiko Hirano, Keiichiro Akamatsu, Masakazu Ichinose
• Journal: American journal of respiratory cell and molecular biology (Am J Respir Cell Mol Biol) Vol. 42 Issue 6 Pg. 651-60 (Jun 2010) ISSN: 1535-4989 [Electronic] United States
• PMID: 19597128 (Publication Type: Journal Article)

Chemical References

• Antioxidants
• CXCL8 protein, human
• Cysteine Proteinase Inhibitors
• Glucocorticoids
• IRF3 protein, human
• Interferon Regulatory Factor-3
• Interleukin-8
• Leupeptins
• Oxidants
• Proteasome Inhibitors
• RELA protein, human
• RNA, Double-Stranded
• TLR3 protein, human
• Toll-Like Receptor 3
• Transcription Factor RelA
• Dexamethasone
• Hydrogen Peroxide
• Proteasome Endopeptidase Complex
• Poly I-C
• benzyloxycarbonylleucyl-leucyl-leucine aldehyde
• Acetylcysteine

Topics

• Acetylcysteine (pharmacology)
• Active Transport, Cell Nucleus
• Antioxidants (pharmacology)
• Cell Line
• Cysteine Proteinase Inhibitors (pharmacology)
• Dexamethasone (pharmacology)
• Dose-Response Relationship, Drug
• Epithelial Cells (drug effects, immunology, metabolism)
• Glucocorticoids (pharmacology)
• Humans
• Hydrogen Peroxide (pharmacology)
• Interferon Regulatory Factor-3 (genetics, metabolism)
• Interleukin-8 (metabolism)
• Leupeptins (pharmacology)
• Oxidants (pharmacology)
• Oxidative Stress (drug effects, genetics)
• Poly I-C (metabolism)
• Proteasome Endopeptidase Complex (metabolism)
• Proteasome Inhibitors
• RNA Interference
• RNA, Double-Stranded (metabolism)
• Respiratory Mucosa (drug effects, immunology, metabolism)
• Time Factors
• Toll-Like Receptor 3 (metabolism)
• Transcription Factor RelA (metabolism)
• Up-Regulation