Stimulation of the ceramide pathway partially mimics lipopolysaccharide-induced responses in murine peritoneal macrophages

Barber, Sheila A.; Detore, Gregory R.; McNally, R; Vogel, Stefanie N.

doi:10.1128/iai.64.8.3397-3400.1996

Cited by 35 publications

(9 citation statements)

References 26 publications

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“…In contrast to C1P, which is not known to affect cytokine production, ceramide is implicated in LPS signalling, as it was shown to be endogenously produced upon LPS stimulation of RAW264.7 macrophages, 49 and to mimic some of the effects of LPS upon exogenous addition 49,50 . Conflicting results have been obtained for the effect of exogenous ceramide on TNF‐α production, with some reports showing induction in unstimulated macrophages, 51,52 and others showing no such effect in either unstimulated or LPS‐stimulated macrophages 49,50 . Interestingly, a recent report using intestinal epithelial cells showed that difluoromethylene analogue of sphingomyelin (SMA)‐7, a C1P derivative with stereochemistry similar to that of PCERA‐1, suppressed LPS‐induced NF‐κB activation and subsequent production of the pro‐inflammatory cytokine IL‐8, by direct inhibition of a ceramide‐producing enzyme, sphingomyelinase 53 .…”

Section: Discussionmentioning

confidence: 99%

A ceramide‐1‐phosphate analogue, PCERA‐1, simultaneously suppresses tumour necrosis factor‐α and induces interleukin‐10 production in activated macrophages

et al. 2009

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SummaryTight regulation of the production of the key pro-inflammatory cytokine tumour necrosis factor-a (TNF-a) is essential for the prevention of chronic inflammatory diseases. In vivo administration of a synthetic phospholipid, named hereafter phospho-ceramide analogue-1 (PCERA-1), was previously found to suppress lipopolysaccharide (LPS)-induced TNF-a blood levels. We therefore investigated the in vitro anti-inflammatory effects of PCERA-1. Here, we show that extracellular PCERA-1 potently suppresses production of the pro-inflammatory cytokine TNF-a in RAW264.7 macrophages, and in addition, independently and reciprocally regulates the production of the anti-inflammatory cytokine interleukin-10 (IL-10). Specificity is demonstrated by the inability of the phospholipids ceramide-1-phosphate (C1P), sphingosine-1-phosphate (S1P) and lysophosphatidic acid (LPA) to perform these activities. Similar TNF-a suppression and IL-10 induction by PCERA-1 were observed in macrophages when activated by Toll-like receptor 4 (TLR4), TLR2 and TLR7 agonists. Regulation of cytokine production is demonstrated at the mRNA and protein levels. Finally, we show that, while PCERA-1 does not block activation of nuclear factor (NF)-jB and mitogen-activated protein kinases by LPS, it elevates the intracellular cAMP level. In conclusion, the antiinflammatory activity of PCERA-1 seems to be mediated by a cell membrane receptor, upstream of cAMP production, and eventually TNF-a suppression and IL-10 induction. Thus, identification of the PCERA-1 receptor may provide new pharmacological means to block inflammation.

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Section: Discussionmentioning

confidence: 99%

A ceramide‐1‐phosphate analogue, PCERA‐1, simultaneously suppresses tumour necrosis factor‐α and induces interleukin‐10 production in activated macrophages

et al. 2009

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“…It is well established that tyrosine kinase inhibitors block LPS-induced proinflammatory cytokine production, and it has been described that IL-10 can inhibit tyrosine kinase activity [79]. It is interesting that some publications suggested that the phosphatase inhibitor okadaic acid can reverse endotoxin tolerance [142][143][144][145]. It would therefore be interesting to see whether induction of PTPN1 would interfere with any of the described tyrosine kinase pathways triggered by LPS (see above).…”

Section: Does Il-10 Induce Genes That Are Known To Regulate Lps Respomentioning

confidence: 99%

New insights into the molecular mechanism of interleukin-10-mediated immunosuppression

Grütz

2004

Journal of Leukocyte Biology

266

168

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Interleukin-10 (IL-10) is an important immunomodulatory cytokine, which has attracted much attention because of its anti-inflammatory properties. It reduces antigen presentation and inhibits T cell activation. IL-10-treated myeloid cells lose their ability to respond toward the endotoxin lipopolysaccharide (LPS) with the production of several proinflammatory mediators. Thereby, IL-10 limits excessive inflammatory reactions in response to endotoxin as it occurs in colitis or endotoxin shock. Mice can be tolerized toward endotoxin shock when pretreated with a sublethal dose of LPS. This can be mimicked in vitro as LPS desensitization, resulting in a similar LPS hyporesponsiveness as observed with IL-10 pretreatment. However, an early block in LPS signaling characterizes LPS desensitization, whereas IL-10 seems to target late events. Controversial reports have been published where IL-10 would interfere with the induction of proinflammatory mediators, and little is known about the molecular mechanisms behind the anti-inflammatory activities of IL-10. Some recent publications have tried to gain more insight into the molecular mechanism of IL-10 by gene-expression profiling and functional studies in myeloid-derived cells. These results are reviewed here and compared with the progress that has been made to understand the induction of endotoxin tolerance by LPS itself.

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“…However, the activity of the dimer (CA) or the free catalytic subunit (C) cannot be stimulated by ceramide (101). Ceramide might be an important second messenger for cell membrane-located receptors (20,252).…”

Section: Sphingosine Derivativesmentioning

confidence: 99%

Effects of Serine/Threonine Protein Phosphatases on Ion Channels in Excitable Membranes

Herzig

Neumann

2000

Physiological Reviews

247

264

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This review deals with the influence of serine/threonine-specific protein phosphatases on the function of ion channels in the plasma membrane of excitable tissues. Particular focus is given to developments of the past decade. Most of the electrophysiological experiments have been performed with protein phosphatase inhibitors. Therefore, a synopsis is required incorporating issues from biochemistry, pharmacology, and electrophysiology. First, we summarize the structural and biochemical properties of protein phosphatase (types 1, 2A, 2B, 2C, and 3-7) catalytic subunits and their regulatory subunits. Then the available pharmacological tools (protein inhibitors, nonprotein inhibitors, and activators) are introduced. The use of these inhibitors is discussed based on their biochemical selectivity and a number of methodological caveats. The next section reviews the effects of these tools on various classes of ion channels (i.e., voltage-gated Ca(2+) and Na(+) channels, various K(+) channels, ligand-gated channels, and anion channels). We delineate in which cases a direct interaction between a protein phosphatase and a given channel has been proven and where a more complex regulation is likely involved. Finally, we present ideas for future research and possible pathophysiological implications.

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Stimulation of the ceramide pathway partially mimics lipopolysaccharide-induced responses in murine peritoneal macrophages

Cited by 35 publications

References 26 publications

A ceramide‐1‐phosphate analogue, PCERA‐1, simultaneously suppresses tumour necrosis factor‐α and induces interleukin‐10 production in activated macrophages

A ceramide‐1‐phosphate analogue, PCERA‐1, simultaneously suppresses tumour necrosis factor‐α and induces interleukin‐10 production in activated macrophages

New insights into the molecular mechanism of interleukin-10-mediated immunosuppression

Effects of Serine/Threonine Protein Phosphatases on Ion Channels in Excitable Membranes

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