Abstract
Influenza A is a highly contagious single-stranded RNA virus that infects both the upper and lower respiratory tracts of humans. The host innate immune Toll-like receptor (TLR) 3 was shown previously in cells of myeloid origin to recognize the viral replicative, intermediate double-stranded RNA (dsRNA). Thus, dsRNA may be critical for the outcome of the infection. Here we first compared the activation triggered by either influenza A virus or dsRNA in pulmonary epithelial cells. We established that TLR3 is constitutively expressed in human alveolar and bronchial epithelial cells, and we describe its intracellular localization. Expression of TLR3 was positively regulated by the influenza A virus and by dsRNA but not by other inflammatory mediators, including bacterial lipopolysaccharide, the cytokines tumor necrosis factor-alpha and interleukin (IL)-1beta, and the protein kinase C activator phorbol 12-myristate 13-acetate. We also demonstrated that TLR3 contributes directly to the immune response of respiratory epithelial cells to influenza A virus and dsRNA, and we propose a molecular mechanism by which these stimuli induce epithelial cell activation. This model involves mitogen-activated protein kinases, phosphatidylinositol 3-kinase/Akt signaling, and the TLR3-associated adaptor molecule TRIF but not MyD88-dependent activation of the transcription factors NF-kappaB or interferon regulatory factor/interferon-sensitive response-element pathways. Ultimately, this signal transduction elicits an epithelial response that includes the secretion of the cytokines IL-8, IL-6, RANTES (regulated on activation normal T cell expressed and secreted), and interferon-beta and the up-regulation of the major adhesion molecule ICAM-1.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing
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Antigens, Differentiation / metabolism
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Cytokines / pharmacology
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Epithelial Cells / cytology
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Epithelial Cells / immunology*
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Epithelial Cells / metabolism*
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Extracellular Signal-Regulated MAP Kinases / metabolism
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Gene Expression Regulation / drug effects
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Humans
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Influenza A virus / immunology*
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Interferons / pharmacology
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Interleukin-1 / pharmacology
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Lipopolysaccharides / pharmacology
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Lung / cytology*
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Membrane Glycoproteins / genetics
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Membrane Glycoproteins / metabolism*
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Myeloid Differentiation Factor 88
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NF-kappa B / metabolism
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Phosphatidylinositol 3-Kinases / metabolism
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Poly I-C / pharmacology
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Protein Serine-Threonine Kinases / metabolism
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Protein Transport
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Proto-Oncogene Proteins / metabolism
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Proto-Oncogene Proteins c-akt
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RNA, Double-Stranded / immunology*
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Receptors, Cell Surface / genetics
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Receptors, Cell Surface / metabolism*
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Receptors, Immunologic / metabolism
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Response Elements / genetics
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Signal Transduction / drug effects
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Tetradecanoylphorbol Acetate / pharmacology
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Toll-Like Receptor 3
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Toll-Like Receptors
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Tumor Necrosis Factor-alpha / pharmacology
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Up-Regulation / drug effects
Substances
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Adaptor Proteins, Signal Transducing
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Antigens, Differentiation
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Cytokines
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Interleukin-1
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Lipopolysaccharides
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MYD88 protein, human
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Membrane Glycoproteins
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Myeloid Differentiation Factor 88
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NF-kappa B
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Proto-Oncogene Proteins
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RNA, Double-Stranded
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Receptors, Cell Surface
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Receptors, Immunologic
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TLR3 protein, human
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Toll-Like Receptor 3
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Toll-Like Receptors
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Tumor Necrosis Factor-alpha
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Interferons
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AKT1 protein, human
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Protein Serine-Threonine Kinases
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Proto-Oncogene Proteins c-akt
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Extracellular Signal-Regulated MAP Kinases
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Tetradecanoylphorbol Acetate
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Poly I-C