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  • Title: Cooperative activation of CCL5 expression by TLR3 and tumor necrosis factor-alpha or interferon-gamma through nuclear factor-kappaB or STAT-1 in airway epithelial cells.
    Author: Homma T, Matsukura S, Hirose T, Ohnishi T, Kimura T, Kurokawa M, Ieki K, Odaka M, Suzuki S, Watanabe S, Sato M, Kawaguchi M, Schleimer RP, Adachi M.
    Journal: Int Arch Allergy Immunol; 2010; 152 Suppl 1(Suppl 1):9-17. PubMed ID: 20523058.
    Abstract:
    BACKGROUND: CCL5/RANTES contributes to prolonged eosinophilic inflammation and asthma exacerbation after a viral infection. We studied the mechanism of CCL5 expression using viral product double-stranded RNA (dsRNA), a ligand of Toll-like receptor 3 (TLR3), and inflammatory cytokines in airway epithelial cells. METHODS: The airway epithelial cell line BEAS-2B was used in our in vitro study, and the levels of CCL5 mRNA and CCL5 protein expression were determined using real-time PCR and ELISA. The activity of the CCL5 promoter region and nuclear factor (NF)-kappaB was assessed by dual luciferase assay using specific luciferase reporter plasmids. We used actinomycin D to assess the stability of mRNA. Phosphorylation of signal transducer and activator of transcription 1 (STAT-1) was analyzed by Western blot. RESULTS: Synthetic dsRNA up-regulated the expression of CCL5 mRNA and CCL5 protein. Adding TNF-alpha or IFN-gamma to dsRNA further increased the expression of CCL5. The combination of TNF-alpha and dsRNA cooperatively activated the CCL5 promoter region and the NF-kappaB-specific reporter. IFN-gamma did not activate these reporters. However, it increased the stability of CCL5 mRNA induced by dsRNA. IFN-gamma phosphorylated STAT-1, but dsRNA did not. The effects of IFN-gamma were not evident in the cells transfected with short interfering RNA for STAT-1. CONCLUSIONS: Cross-talk between TLR3 signaling and inflammatory cytokines regulates the expression of CCL5 in airway epithelial cells. In this mechanism, TNF-alpha may activate NF-kappaB, in cooperation with TLR3 signaling. IFN-gamma may stabilize CCL5 mRNA up-regulated by TLR3. This mechanism may depend on STAT-1.
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