Abstract
Pneumococcal lung infections represent a major cause of death worldwide. Single nucleotide polymorphisms (SNPs) in the NFKBIZ gene, encoding the transcription factor IκBζ, are associated with increased susceptibility to invasive pneumococcal disease. We hence analyzed how IκBζ might regulate inflammatory responses to pneumococcal infection. We first demonstrate that IκBζ is expressed in human blood monocytes but not in bronchial epithelial cells, in response to wild type pneumococcal strain D39. D39 transiently induced IκBζ in a dose dependent manner, with subsequent induction of downstream molecules involved in host defense. Of these molecules, IκBζ knockdown reduced the expression of IL-6 and GMCSF. Furthermore, IκBζ overexpression increased the activity of IL-6 and GMCSF promoters, supporting the knockdown findings. Pneumococci lacking either pneumolysin or capsule still induced IκBζ. While inhibition of TLR1/TLR2 blocked D39 induced IκBζ expression, TLR4 inhibition did not. Blockade of p38 MAP kinase and NFκB suppressed D39 induced IκBζ. Overall, our data demonstrates that IκBζ regulates monocyte inflammatory responses to Streptococcus pneumoniae by promoting the production of IL-6 and GMCSF.
MeSH terms
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Adaptor Proteins, Signal Transducing
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Benzocycloheptenes / pharmacology
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Bronchi / drug effects
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Bronchi / immunology
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Bronchi / microbiology
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Epithelial Cells / drug effects
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Epithelial Cells / immunology*
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Epithelial Cells / microbiology
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Gene Expression Regulation
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Granulocyte-Macrophage Colony-Stimulating Factor / genetics
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Granulocyte-Macrophage Colony-Stimulating Factor / immunology
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Host-Pathogen Interactions*
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Humans
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I-kappa B Proteins / antagonists & inhibitors
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I-kappa B Proteins / genetics
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I-kappa B Proteins / immunology*
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Interleukin-6 / genetics
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Interleukin-6 / immunology
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Lipopolysaccharides / pharmacology
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Monocytes / drug effects
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Monocytes / immunology*
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Monocytes / microbiology
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NF-kappa B / genetics
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NF-kappa B / immunology
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Nuclear Proteins / antagonists & inhibitors
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Nuclear Proteins / genetics
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Nuclear Proteins / immunology*
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Primary Cell Culture
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RNA, Small Interfering / genetics
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RNA, Small Interfering / immunology
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Signal Transduction
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Streptococcus pneumoniae / drug effects
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Streptococcus pneumoniae / physiology*
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Toll-Like Receptor 1 / antagonists & inhibitors
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Toll-Like Receptor 1 / genetics
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Toll-Like Receptor 1 / immunology
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Toll-Like Receptor 2 / antagonists & inhibitors
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Toll-Like Receptor 2 / genetics
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Toll-Like Receptor 2 / immunology
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Toll-Like Receptor 4 / antagonists & inhibitors
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Toll-Like Receptor 4 / genetics
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Toll-Like Receptor 4 / immunology
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p38 Mitogen-Activated Protein Kinases / genetics
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p38 Mitogen-Activated Protein Kinases / immunology
Substances
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Adaptor Proteins, Signal Transducing
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Benzocycloheptenes
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I-kappa B Proteins
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IL6 protein, human
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Interleukin-6
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Lipopolysaccharides
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NF-kappa B
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NFKBIZ protein, human
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Nuclear Proteins
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RNA, Small Interfering
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TLR2 protein, human
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TLR4 protein, human
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Toll-Like Receptor 1
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Toll-Like Receptor 2
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Toll-Like Receptor 4
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Granulocyte-Macrophage Colony-Stimulating Factor
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p38 Mitogen-Activated Protein Kinases