Abstract
Mucosal epithelial cells in the respiratory tract act as the first line of host innate defense against inhaled microbes by producing a range of molecules for clearance. In particular, epithelial mucins facilitate the mucociliary clearance by physically trapping the inhaled microbes. Up-regulation of mucin production thus represents an important host innate defense response against invading microbes. Excess mucin production, however, overwhelms the mucociliary clearance, resulting in defective mucosal defenses. Thus, tight regulation of mucin production is critical for maintaining an appropriate balance between beneficial and detrimental outcomes. Among various mechanisms, negative regulation plays an important role in tightly regulating mucin production. Here we show that the PAK4-JNK signaling pathway acted as a negative regulator for Streptococcus pneumoniae pneumolysin-induced MUC5AC mucin transcription. Moreover pneumolysin also selectively induced expression of MKP1 via a TLR4-dependent MyD88-TRAF6-ERK signaling pathway, which inhibited the PAK4-JNK signaling pathway, thereby leading to up-regulation of MUC5AC mucin production to maintain effective mucosal protection against S. pneumoniae infection. These studies provide novel insights into the molecular mechanisms underlying the tight regulation of mucin overproduction in the pathogenesis of airway infectious diseases and may lead to development of new therapeutic strategies.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Animals
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Bacterial Proteins / immunology
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Bacterial Proteins / metabolism
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Bacterial Proteins / pharmacology
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Dual Specificity Phosphatase 1 / genetics
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Dual Specificity Phosphatase 1 / immunology
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Dual Specificity Phosphatase 1 / metabolism*
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HeLa Cells
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Humans
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Immunity, Innate / drug effects
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Immunity, Innate / genetics
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Immunity, Innate / immunology
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Immunity, Mucosal
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MAP Kinase Kinase 4 / genetics
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MAP Kinase Kinase 4 / immunology
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MAP Kinase Kinase 4 / metabolism*
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Mice
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Mice, Mutant Strains
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Mucin 5AC / biosynthesis*
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Mucin 5AC / genetics
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Mucin 5AC / immunology
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Myeloid Differentiation Factor 88
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Pneumococcal Infections / genetics
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Pneumococcal Infections / immunology
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Pneumococcal Infections / metabolism*
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Respiratory Mucosa / immunology
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Respiratory Mucosa / metabolism*
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Signal Transduction / drug effects*
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Signal Transduction / immunology
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Streptococcus pneumoniae* / immunology
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Streptococcus pneumoniae* / metabolism
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Streptolysins / immunology
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Streptolysins / metabolism
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Streptolysins / pharmacology*
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TNF Receptor-Associated Factor 6
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Toll-Like Receptor 4 / genetics
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Toll-Like Receptor 4 / immunology
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Toll-Like Receptor 4 / metabolism
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Transcription, Genetic / drug effects
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Transcription, Genetic / genetics
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Transcription, Genetic / immunology
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Up-Regulation / drug effects
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Up-Regulation / genetics
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Up-Regulation / immunology
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p21-Activated Kinases / genetics
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p21-Activated Kinases / immunology
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p21-Activated Kinases / metabolism*
Substances
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Bacterial Proteins
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MUC5AC protein, human
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MYD88 protein, human
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Muc5ac protein, mouse
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Mucin 5AC
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Myd88 protein, mouse
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Myeloid Differentiation Factor 88
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Streptolysins
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TLR4 protein, human
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TNF Receptor-Associated Factor 6
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Tlr4 protein, mouse
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Toll-Like Receptor 4
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plY protein, Streptococcus pneumoniae
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PAK4 protein, human
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Pak4 protein, mouse
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p21-Activated Kinases
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MAP Kinase Kinase 4
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DUSP1 protein, human
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Dual Specificity Phosphatase 1
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Dusp1 protein, mouse