Abstract
Mycoplasma genitalium is a leading pathogen of nongonoccocal chlamydia-negative urethritis, which has been implicated directly in numerous other genitourinary and extragenitourinary tract pathologies. The pathogenesis of infection is attributed in part to excessive immune responses. M. genitalium-derived lipid-associated membrane proteins (LAMPs) are a mixture of bacterial lipoproteins, exposed at the surface of mycoplasma, that are potent inducers of the host innate immune system. However, the interaction of M. genitalium-derived LAMPs as pathogenic agents with Toll-like receptors (TLRs) and the signaling pathways responsible for active inflammation and NF-kappaB activation have not been fully elucidated. In this study, LAMPs induced the production of tumor necrosis factor alpha (TNF-alpha) and interleukin-6 (IL-6) in a dose-dependent manner. Blocking assays showed that TLR2- and CD14-neutralizing antibodies reduced the expression of TNF-alpha and IL-6 in THP-1 cells. Furthermore, LAMP-induced NF-kappaB activation was increased in 293T cells transfected with TLR2 plasmid. The activity of NF-kappaB was synergically augmented by cotransfected TLR1, TLR6, and CD14. Additionally, LAMPs were shown to inhibit NF-kappaB expression by cotransfection with dominant-negative MyD88 and TLR2 plasmids. These results suggest that M. genitalium-derived LAMPs activate NF-kappaB via TLR1, TLR2, TLR6, and CD14 in a MyD88-dependent pathway.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Antibodies, Monoclonal / pharmacology
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Bacterial Proteins / pharmacology
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Cell Line
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Humans
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Immunologic Factors / pharmacology
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Interleukin-6 / antagonists & inhibitors
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Interleukin-6 / immunology
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Interleukin-6 / metabolism
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Lipopolysaccharide Receptors / drug effects
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Lipopolysaccharide Receptors / immunology*
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Lipopolysaccharide Receptors / metabolism
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Lipopolysaccharides / pharmacology
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Membrane Glycoproteins / immunology
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Membrane Glycoproteins / metabolism
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Mycoplasma Infections / immunology*
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Mycoplasma genitalium / immunology*
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Mycoplasma genitalium / metabolism
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NF-kappa B / agonists
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NF-kappa B / immunology*
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NF-kappa B / metabolism
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Receptors, Interleukin-1 / immunology
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Receptors, Interleukin-1 / metabolism
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Toll-Like Receptor 1 / immunology*
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Toll-Like Receptor 1 / metabolism
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Toll-Like Receptor 2 / antagonists & inhibitors
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Toll-Like Receptor 2 / immunology*
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Toll-Like Receptor 2 / metabolism
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Toll-Like Receptor 6 / immunology*
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Toll-Like Receptor 6 / metabolism
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Transfection
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Tumor Necrosis Factor-alpha / antagonists & inhibitors
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Tumor Necrosis Factor-alpha / immunology
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Tumor Necrosis Factor-alpha / metabolism
Substances
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Antibodies, Monoclonal
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Bacterial Proteins
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IL6 protein, human
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Immunologic Factors
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Interleukin-6
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Lipopolysaccharide Receptors
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Lipopolysaccharides
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Membrane Glycoproteins
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NF-kappa B
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Receptors, Interleukin-1
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TIRAP protein, human
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TLR2 protein, human
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TLR6 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 6
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Tumor Necrosis Factor-alpha