Abstract
Mammalian Toll-like receptors (TLRs) recognize microbial pathogen-associated molecular patterns and are critical for innate immunity against microbial infection. Diacylglycerol (DAG) kinases (DGKs) regulate the intracellular levels of two important second messengers involved in signaling from many surface receptors by converting DAG to phosphatidic acid (PA). We demonstrate that the zeta isoform of the DGK family (DGKzeta) is expressed in macrophages (Mphi) and dendritic cells. DGKzeta deficiency results in impaired interleukin (IL) 12 and tumor necrosis factor alpha production following TLR stimulation in vitro and in vivo, increased resistance to endotoxin shock, and enhanced susceptibility to Toxoplasma gondii infection. We further show that DGKzeta negatively controls the phosphatidylinositol 3-kinase (PI3K)-Akt pathway and that inhibition of PI3K activity or treatment with PA can restore lipopolysaccharide-induced IL-12 production by DGKzeta-deficient Mphi. Collectively, our data provide the first genetic evidence that an enzyme involved in DAG/PA metabolism plays an important role in innate immunity and indicate that DGKzeta promotes TLR responses via a pathway involving inhibition of PI3K.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Cells, Cultured
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Dendritic Cells / enzymology
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Diacylglycerol Kinase / deficiency
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Diacylglycerol Kinase / genetics
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Diacylglycerol Kinase / metabolism*
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Enzyme Activation
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Gene Expression Regulation, Enzymologic
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I-kappa B Proteins / metabolism
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Interleukin-12 / biosynthesis
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Lipopolysaccharides / pharmacology
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Macrophages / drug effects
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Macrophages / enzymology
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Mice
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Mice, Knockout
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Mitogen-Activated Protein Kinases / metabolism
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Phosphatidic Acids / pharmacology
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Phosphatidylinositol 3-Kinases / metabolism
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Proto-Oncogene Proteins c-akt / metabolism
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Signal Transduction
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Survival Rate
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Th1 Cells / enzymology
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Th1 Cells / immunology
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Th1 Cells / parasitology
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Toll-Like Receptors / metabolism
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Toxoplasma / immunology*
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Toxoplasmosis / enzymology*
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Toxoplasmosis / immunology*
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Toxoplasmosis / parasitology
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Toxoplasmosis / pathology
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Tumor Necrosis Factor-alpha / biosynthesis
Substances
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I-kappa B Proteins
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Lipopolysaccharides
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Phosphatidic Acids
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Toll-Like Receptors
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Tumor Necrosis Factor-alpha
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Interleukin-12
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Phosphatidylinositol 3-Kinases
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Diacylglycerol Kinase
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diacylglycerol kinase zeta, mouse
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Proto-Oncogene Proteins c-akt
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Mitogen-Activated Protein Kinases