Pertussis toxin promotes macrophage survival through inhibition of acid sphingomyelinase and activation of the phosphoinositide 3-kinase/protein kinase B pathway

Wang, Shih‐Wei; Parhar, Kuljit; Chiu, Kai Jen; Tran, Anthony; Gangoiti, Patricia; Kong, Jennifer Y.; Gonzalez-Lopez, Monika; Salh, Bill; Duronio, Vincent; Steinbrecher, Urs P.; Gómez-Muñoz, Antonio

doi:10.1016/j.cellsig.2007.04.001

Cited by 16 publications

(10 citation statements)

References 43 publications

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“…We have also observed a similar effect in murine macrophagelike cells (RAW264.7) upon treatment with LPS (data not shown). Similar down-regulation of sphingomyelinase activity by pertussis toxin, also a Toll-like receptor 4 ligand, had been described by Wang et al (2007), who showed that the pertussis toxin treatment prolongs macrophages survival by inhibiting acid sphingomyelinase activity. The effect of the LXR agonists on SMPDL3A expression does not depend on the stimulation of THP-1 macrophages with LPS.…”

Section: Discussionsupporting

confidence: 76%

Regulation of Sphingomyelin Phosphodiesterase Acid-Like 3A Gene (SMPDL3A) by Liver X Receptors

et al. 2012

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Liver X receptor (LXR) ␣ and LXR␤ function as physiological sensors of cholesterol metabolites (oxysterols), regulating key genes involved in cholesterol and lipid metabolism. LXRs have been extensively studied in both human and rodent cell systems, revealing their potential therapeutic value in the contexts of atherosclerosis and inflammatory diseases. The LXR genome landscape has been investigated in murine macrophages but not in human THP-1 cells, which represent one of the frequently used monocyte/macrophage cell systems to study immune responses. We used a whole-genome screen to detect direct LXR target genes in THP (GW3965)]. This screen identified the sphingomyelin phosphodiesterase acid-like 3A (SMPDL3A) gene as a novel LXR-regulated gene, with an LXR response element within its promoter. We investigated the regulation of SMPDL3A gene expression by LXRs across several human and mouse cell types. These studies indicate that the induction of SMPDL3A is LXR-dependent and is restricted to human blood cells with no induction observed in mouse cellular systems.

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Section: Discussionsupporting

confidence: 76%

Regulation of Sphingomyelin Phosphodiesterase Acid-Like 3A Gene (SMPDL3A) by Liver X Receptors

et al. 2012

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“…With this procedure, healthy cells remained unstained whereas annexin V-FITC stained early apoptotic cells, propidium iodide and annexin V-FITC stained late apoptotic cells and propidium iodide stained necrotic cells. Samples were analyzed by flow cytometry with an air-cooled 488 nm argon-ion laser (FACSCalibur, BD Biosciences) and CellQuest software (BD Bioscences), essentially as described [22].…”

Section: Methodsmentioning

confidence: 99%

Ceramide 1-phosphate stimulates proliferation of C2C12 myoblasts

et al. 2012

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Recent studies have established specific cellular functions for different bioactive sphingolipids in skeletal muscle cells. Ceramide 1-phosphate (C1P) is an important bioactive sphingolipid that has been involved in cell growth and survival. However its possible role in the regulation of muscle cell homeostasis has not been so far investigated. In this study, we show that C1P stimulates myoblast proliferation, as determined by measuring the incorporation of tritiated thymidine into DNA, and progression of the myoblasts through the cell cycle. C1P induced phosphorylation of glycogen synthase kinase-3β and the product of retinoblastoma gene, and enhanced cyclin D1 protein levels. The mitogenic action of C1P also involved activation of phosphatidylinositol 3-kinase/Akt, ERK1/2 and the mammalian target of rapamycin. These effects of C1P were independent of interaction with a putative Gi-coupled C1P receptor as pertussis toxin, which maintains Gi protein in the inactive form, did not affect C1P-stimulated myoblast proliferation. By contrast, C1P was unable to inhibit serum starvation- or staurosporine-induced apoptosis in the myoblasts, and did not affect myogenic differentiation. Collectively, these results add up to the current knowledge on cell types targeted by C1P, which so far has been mainly confined to fibroblasts and macrophages, and extend on the mechanisms by which C1P exerts its mitogenic effects. Moreover, the biological activities of C1P described in this report establish that this phosphosphingolipid may be a relevant cue in the regulation of skeletal muscle regeneration, and that C1P-metabolizing enzymes might be important targets for developing cellular therapies for treatment of skeletal muscle degenerative diseases, or tissue injury.

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“…This suggests that GnRH receptor signaling through G a s and adenylate cyclase may be contextually different from the effects of exogenous 8-Br-cAMP. Previous data obtained using pertussis toxin to inhibit G ai may be misleading in view of the recent discovery that the toxin is also an inhibitor of acid sphingomyelinase and ceramide production (48).…”

Section: Inhibition Of Cellular Camentioning

confidence: 99%

Gonadotropin-Releasing Hormone Receptor Levels and Cell Context Affect Tumor Cell Responses to AgonistIn vitroandIn vivo

et al. 2008

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Activation of gonadotropin-releasing hormone (GnRH) receptors inhibits proliferation of transformed cells derived from reproductive tissues and in transfected cell lines. Hence, GnRH receptors represent a therapeutic target for direct action of GnRH analogues on certain proliferating cells. However, more cell biological data are required to develop this particular application of GnRH analogues. Therefore, we compared the effects of GnRH receptor activation in transfected HEK293 cells (HEK293 [SCL60] ) with transfected human ovarian cancer cell lines SKOV3 and EFO21, human hepatoblastoma HepG2 cells, and rat neuroblastoma B35 cells. Marked differences in receptor levels, magnitude of inositol phosphate generation, and dynamics of inositol phosphate turnover occurred in the different cells. Activation of GnRH receptors, expressed at high or moderate levels, inhibited the growth of HEK293 [SCL60] and B35 cells, respectively. Western blotting detected markers of apoptosis [cleaved poly(ADP-ribose) polymerase, caspase-9] in HEK293 [SCL60] and B35 following treatment with 100 nmol/L D-Trp 6 -GnRH

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Pertussis toxin promotes macrophage survival through inhibition of acid sphingomyelinase and activation of the phosphoinositide 3-kinase/protein kinase B pathway

Cited by 16 publications

References 43 publications

Regulation of Sphingomyelin Phosphodiesterase Acid-Like 3A Gene (SMPDL3A) by Liver X Receptors

Regulation of Sphingomyelin Phosphodiesterase Acid-Like 3A Gene (SMPDL3A) by Liver X Receptors

Ceramide 1-phosphate stimulates proliferation of C2C12 myoblasts

Gonadotropin-Releasing Hormone Receptor Levels and Cell Context Affect Tumor Cell Responses to AgonistIn vitroandIn vivo

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