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Diacylglycerol kinase regulates microbial recognition and host resistance to Toxoplasma gondii

¹ Department of Pediatrics–Allergy and Immunology and ² Department of Immunology, Duke University Medical Center, Durham, NC 27710
³ Division of Molecular Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229
⁴ Children's Hospital of Philadelphia, Philadelphia, PA 19104

CORRESPONDENCE Xiao-Ping Zhong: zhong001{at}mc.duke.edu

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 isoform of the DGK family (DGK) is expressed in macrophages (M) and dendritic cells. DGK deficiency results in impaired interleukin (IL) 12 and tumor necrosis factor 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 DGK 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 DGK-deficient M. 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 DGK promotes TLR responses via a pathway involving inhibition of PI3K.

Abbreviations used: BMM, bone marrow–derived M DAG, diacylglycerol; DGK, DAG kinase; H&E, hematoxylin and eosin; LCMV, lymphocytic choriomeningitis virus; MAPK, mitogen-associated protein kinase; M, macrophage(s); MyD88, myeloid differentiation primary response protein 88; PA, phosphatidic acid; PI3K, phosphatidylinositol 3–kinase; PIP₃, phosphatidylinositol (3,4,5)-trisphosphate; PKC, protein kinase C; RasGRP, Ras guanyl nucleotide-releasing protein; SHP-1, Src homology 2 domain–containing phosphatase 1; STAg, T. gondii–soluble tachyzoite Ag; TLR, Toll-like receptor.

C.-H. Liu, F.S. Machado, and R. Guo contributed equally to this work.

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This article has been cited by other articles:

• Wattenberg, B. W., Raben, D. M. (2007). Diacylglycerol Kinases Put the Brakes on Immune Function. Sci Signal 2007: pe43-pe43 [Abstract] [Full Text]  

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