Abstract
In human monocytes and macrophages, interferon-gamma (IFNgamma) augmented mRNA and surface expression of toll-like receptor 4 (TLR4), a crucial component of the signaling receptor complex for bacterial lipopolysaccharide (LPS). Expression of the accessory component MD-2 and of the adapter protein MyD88 was also increased. LPS increased TLR4 mRNA levels, but concomitantly decreased its surface expression. IFNgamma counteracted the LPS-induced downregulation of TLR4. IFNgamma-primed monocytes showed increased responsiveness to LPS in terms of phosphorylation of the interleukin-1 receptor-associated kinase (IRAK; immediately downstream of the MyD88 adapter protein), NF-kB DNA binding activity, and, accordingly, of cytokine (tumor necrosis factor alpha [TNFalpha] and interleukin-12 [IL-12]) production. These results suggest that enhanced TLR4 expression underlies the long-known priming by IFNgamma of mononuclear phagocytes for pathogen recognition and killing as well as its synergism with LPS in macrophage activation.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Antigens, Surface / drug effects
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Antigens, Surface / metabolism
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Carrier Proteins / drug effects
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Carrier Proteins / metabolism
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Drosophila Proteins*
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Drug Synergism
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Humans
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Interferon-gamma / pharmacology*
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Interleukin-1 Receptor-Associated Kinases
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Interleukin-12 / biosynthesis
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Lipopolysaccharides / pharmacology
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Lymphocyte Antigen 96
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Membrane Glycoproteins / drug effects
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Membrane Glycoproteins / metabolism*
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NF-kappa B / drug effects
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NF-kappa B / metabolism
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Phagocytes / drug effects
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Phagocytes / metabolism*
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Protein Kinases / drug effects
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Protein Kinases / metabolism
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Receptors, Cell Surface / drug effects
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Receptors, Cell Surface / metabolism*
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Receptors, Interleukin-1*
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Toll-Like Receptor 4
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Toll-Like Receptors
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Up-Regulation / drug effects
Substances
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Antigens, Surface
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Carrier Proteins
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Drosophila Proteins
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LY96 protein, human
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Lipopolysaccharides
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Lymphocyte Antigen 96
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Membrane Glycoproteins
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NF-kappa B
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Receptors, Cell Surface
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Receptors, Interleukin-1
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TIRAP protein, human
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TLR4 protein, human
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Toll-Like Receptor 4
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Toll-Like Receptors
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Interleukin-12
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Interferon-gamma
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Protein Kinases
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Interleukin-1 Receptor-Associated Kinases