Impaired degranulation but enhanced cytokine production after FcεRI stimulation of diacylglycerol kinase ζ–deficient mast cells

Olenchock, Benjamin A.; Guo, Rishu; Silverman, Michael A.; Wu, Jiansheng; Carpenter, Jeffery H.; Koretzky, Gary A.; Zhong, Xiao‐Ping

doi:10.1083/jcb1735oia10

Cited by 4 publications

(14 citation statements)

References 59 publications

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“…However, PMA plus ionomycin stimulation induces a similar level of β‐hexosaminidase release in WT and DGKζ‐deficient BMMCs, suggesting that the defect causing impairment of mast cell degranulation in DGKζ‐deficient BMMCs is proximal to DAG and Ca 2+ . The impairment of mast cell degranulation has been confirmed by measurement of PCA responses, which are much weaker in DGKζ‐deficient mice than in WT mice (77).…”

Section: Regulating Fcɛri Signaling and Mast Cell Function By Dgkζmentioning

confidence: 87%

“…Using DGKζ‐deficient BMMCs, Olenchock et al (77) investigated how deficiency of this specific DGK isoform may affect mast cell activation. Similar numbers of mast cells have been detected in multiple tissues in DGKζ‐deficient mice as compared with WT mice.…”

Section: Regulating Fcɛri Signaling and Mast Cell Function By Dgkζmentioning

confidence: 99%

“…When stimulating IgE‐loaded DGKζ‐deficient BMMCs through the FcɛRI, PA production is decreased by approximately 50% compared with that observed in WT BMMCs, indicating that DGKζ is involved in the conversion of DAG to PA in mast cells following crosslinking of FcɛRI. Ras, Mek1/2, and Erk1/2 activation are enhanced in DGKζ‐deficient BMMCs following FcɛRI crosslinking (77). Since RasGRP1 is important for PI3K activation but dispensable for Erk1/2 activation (141), this observation suggests that DAG may promote Erk1/2 activation through other effector molecules.…”

Section: Regulating Fcɛri Signaling and Mast Cell Function By Dgkζmentioning

confidence: 99%

“…The decreases of PLCγ phosphorylation is correlated with decreases of PLCγ enzyme activity as both IP 3 production and Ca 2+ responses are decreased in DGKζ‐deficient BMMCs following FcɛRI engagement. Pretreatment of IgE‐sensitized WT BMMCs with PMA or 1,2‐dioctanoyl‐ sn ‐glycerol can also greatly inhibit Ca 2+ flux following subsequent FcɛRI crosslinking (77, 147). Thus, elevated DAG concentration, due either to the addition of DAG analogues or to decreased DAG inactivation in the absence of DGKζ, can inhibit FcɛRI‐induced Ca 2+ flux in mast cells.…”

Section: Regulating Fcɛri Signaling and Mast Cell Function By Dgkζmentioning

confidence: 99%

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Diacylglycerol kinases in immune cell function and self‐tolerance

Zhong

Guo

Zhou

et al. 2008

Immunological Reviews

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Summary Both diacylglycerol (DAG) and phosphatidic acid (PA) are important second messengers involved in signal transduction from many immune cell receptors and can be generated and metabolized through multiple mechanisms. Recent studies indicate that diacylglycerol kinases (DGKs), the enzymes that catalyze phosphorylation of DAG to produce PA, play critical roles in regulating the functions of multiple immune cell lineages. In T cells, two DGK isoforms, α and ζ, inhibit DAG-mediated signaling following T cell receptor engagement and prevent T cell hyperactivation. DGKα and ζ synergistically promote T cell anergy and are critical for T cell tolerence. In mast cells, DGKζ plays differential roles in their activation by promoting degranulation but attenuating cytokine production following enagement of the high affinity receptor for IgE. In dendritic cells and macrophages, DGKζ positively regulates Toll-like receptor-induced proinflammatory cytokine production through its product PA, and is critical for host defense against Toxoplama gondii infection. These studies demonstrate pivotal roles of DGKs in regulating immune cell function by acting both as signal terminator and initiator.

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Section: Regulating Fcɛri Signaling and Mast Cell Function By Dgkζmentioning

confidence: 87%

Section: Regulating Fcɛri Signaling and Mast Cell Function By Dgkζmentioning

confidence: 99%

Section: Regulating Fcɛri Signaling and Mast Cell Function By Dgkζmentioning

confidence: 99%

Section: Regulating Fcɛri Signaling and Mast Cell Function By Dgkζmentioning

confidence: 99%

See 2 more Smart Citations

Diacylglycerol kinases in immune cell function and self‐tolerance

Zhong

Guo

Zhou

et al. 2008

Immunological Reviews

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“…Some investigators have suggested that the activation pattern is transient. For example, Olenchock et al showed that upon FCεRI crosslinking, ERK activation peaked at 30 s and declined after 2 min [11]. When RBL-2H3 cells were studied, ERK activation was transient, peaking at 6 min and was completed by 15 min [8,9].…”

Section: Discussionmentioning

confidence: 97%

Characterization of ERK Activation in Human Mast Cells Stimulated by Contact with T Cells

et al. 2009

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Close physical proximity between mast cells and T cells has been demonstrated in several human conditions. We have identified and characterized a novel mast cell activation pathway initiated by contact with T cells, and showed that this pathway is associated with cytokine release. It has been shown recently that Ras is activated in this pathway. Thus, in the present study we further explore the downstream events associated with Ras activation and cytokine release in human mast cells stimulated by contact with T cells. ERK activation in human mast cells stimulated by either contact with T cells or by crosslinking the FC epsilon receptor was studied. Photobleaching experiments were used to study ERK localization. Enzyme linked immunosorbent assay was used to study the cytokine release by human mast cells. We show that stimulation of human mast cells by contact with activated T cells results is sustained ERK activation. Furthermore, sustained ERK activation in these cells is associated with increased dwell time at the nucleus and with IL-8 release. Interestingly, when mast cells were stimulated by crosslinking the FC epsilon receptor I, ERK activation was transient. ERK activation was associated with a shorter dwell time at the nucleus and with TNF-alpha release. Thus, retaining ERK in the nucleus might be a mechanism utilized by human mast cells to generate different cytokines from a single signaling cascade.

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Diacylglycerol kinase ζ regulates microbial recognition and host resistance to Toxoplasma gondii

Liu

Machado

Guo

et al. 2007

The Journal of Experimental Medicine

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

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Impaired degranulation but enhanced cytokine production after FcεRI stimulation of diacylglycerol kinase ζ–deficient mast cells

Cited by 4 publications

References 59 publications

Diacylglycerol kinases in immune cell function and self‐tolerance

Diacylglycerol kinases in immune cell function and self‐tolerance

Characterization of ERK Activation in Human Mast Cells Stimulated by Contact with T Cells

Diacylglycerol kinase ζ regulates microbial recognition and host resistance to Toxoplasma gondii

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