Abstract
Mucin overproduction is a hallmark of nontypeable Haemophilus influenzae (NTHi) infections. The molecular mechanisms underlying up-regulation of mucin in NTHi infections especially during the initial phase remain unknown. Here we show that P6, a 16-kDa outer membrane lipoprotein well conserved in NTHi, up-regulates MUC5AC mucin gene transcription in vitro and in vivo. Moreover, P6 induces MUC5AC transcription via TLR2-MyD88-IRAK1-TRAF6-TAK1-dependent p38 MAPK-AP1 and IKKbeta-IkappaBalpha-NF-kappaB signaling pathways. This study may bring new insights into the molecular pathogenesis of NTHi-induced infections and lead to novel therapeutic intervention for inhibiting mucin overproduction in patients with NTHi infections.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Blotting, Western
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Cell Membrane / metabolism
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Cells, Cultured
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DNA Primers / chemistry
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Enzyme Activation
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Haemophilus influenzae
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Humans
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I-kappa B Kinase
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I-kappa B Proteins / metabolism*
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Lipoproteins / chemistry*
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Luciferases / metabolism
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MAP Kinase Kinase Kinases / metabolism*
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Membrane Glycoproteins / metabolism*
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Mice
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Mice, Inbred BALB C
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Models, Biological
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Mucin 5AC
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Mucins / metabolism*
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NF-KappaB Inhibitor alpha
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NF-kappa B / metabolism*
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Plasmids / metabolism
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Protein Serine-Threonine Kinases / metabolism*
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Receptors, Cell Surface / metabolism*
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Reverse Transcriptase Polymerase Chain Reaction
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Signal Transduction*
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Toll-Like Receptor 2
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Toll-Like Receptors
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Transcription Factor AP-1 / metabolism*
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Transcription, Genetic*
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Transfection
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Up-Regulation
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p38 Mitogen-Activated Protein Kinases / metabolism*
Substances
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DNA Primers
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I-kappa B Proteins
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Lipoproteins
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MUC5AC protein, human
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Membrane Glycoproteins
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Muc5ac protein, mouse
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Mucin 5AC
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Mucins
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NF-kappa B
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NFKBIA protein, human
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Nfkbia protein, mouse
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Receptors, Cell Surface
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TLR2 protein, human
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Toll-Like Receptor 2
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Toll-Like Receptors
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Transcription Factor AP-1
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NF-KappaB Inhibitor alpha
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Luciferases
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Protein Serine-Threonine Kinases
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CHUK protein, human
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Chuk protein, mouse
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I-kappa B Kinase
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IKBKB protein, human
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IKBKE protein, human
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Ikbkb protein, mouse
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Ikbke protein, mouse
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p38 Mitogen-Activated Protein Kinases
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MAP Kinase Kinase Kinases
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MAP kinase kinase kinase 7