Diacylglycerol kinase zeta regulates microbial recognition and host resistance to Toxoplasma gondii.
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.
Liu
Cheng-Hu
CH
Department of Pediatrics-Allergy and Immunology, Duke University Medical Center, Durham, NC 27710, USA.
Machado
Fabiana S
FS
Guo
Rishu
R
Nichols
Kim E
KE
Burks
A Wesley
AW
Aliberti
Julio C
JC
Zhong
Xiao-Ping
XP
D000818:Animals; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000201:enzymology; D019852:Diacylglycerol Kinase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D004789:Enzyme Activation; D015971:Gene Expression Regulation, Enzymologic; D020672:I-kappa B Proteins / Q000378:metabolism; D018664:Interleukin-12 / Q000096:biosynthesis; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000201:enzymology; D051379:Mice; D018345:Mice, Knockout; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010712:Phosphatidic Acids / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction; D015996:Survival Rate; D018417:Th1 Cells / Q000201:enzymology / Q000276:immunology / Q000469:parasitology; D051193:Toll-Like Receptors / Q000378:metabolism; D014122:Toxoplasma / Q000276:immunology*; D014123:Toxoplasmosis / Q000201:enzymology* / Q000276:immunology* / Q000469:parasitology / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D020672:I-kappa B Proteins; D008070:Lipopolysaccharides; D010712:Phosphatidic Acids; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha; D018664:Interleukin-12; D019869:Phosphatidylinositol 3-Kinases; D019852:Diacylglycerol Kinase; C512480:diacylglycerol kinase zeta, mouse; D051057:Proto-Oncogene Proteins c-akt; D020928:Mitogen-Activated Protein Kinases