Nitric oxide inhibits tumor necrosis factor-α-induced apoptosis by reducing the generation of ceramide

Nadaï, C. De; Sestili, Piero; Cantoni, Orazio; Lièvremont, Jean Philippe; Sciorati, Clara; Barsacchi, Rico; Moncada, Salvador; Meldolesi, Jacopo; Clementi, Emilio

doi:10.1073/pnas.070062397

Cited by 103 publications

(65 citation statements)

References 38 publications

(63 reference statements)

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“…U937, L6, and PC12 cells were cultured essentially as described (22)(23)(24). At day 0, U937 cells were suspended at a density of 3 ϫ 10 4 cells per ml, whereas L6 This paper was submitted directly (Track II) to the PNAS office.…”

Section: Methodsmentioning

confidence: 99%

Mitochondrial biogenesis by NO yields functionally active mitochondria in mammals

Nisoli

Falcone

Tonello

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

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We recently found that long-term exposure to nitric oxide (NO) triggers mitochondrial biogenesis in mammalian cells and tissues by activation of guanylate cyclase and generation of cGMP. Here, we report that the NO/cGMP-dependent mitochondrial biogenesis is associated with enhanced coupled respiration and content of ATP in U937, L6, and PC12 cells. The observed increase in ATP content depended entirely on oxidative phosphorylation, because ATP formation by glycolysis was unchanged. Brain, kidney, liver, heart, and gastrocnemius muscle from endothelial NO synthase null mutant mice displayed markedly reduced mitochondrial content associated with significantly lower oxygen consumption and ATP content. In these tissues, ultrastructural analyses revealed significantly smaller mitochondria. Furthermore, a significant reduction in the number of mitochondria was observed in the subsarcolemmal region of the gastrocnemius muscle. We conclude that NO/cGMP stimulates mitochondrial biogenesis, both in vitro and in vivo, and that this stimulation is associated with increased mitochondrial function, resulting in enhanced formation of ATP

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Section: Methodsmentioning

confidence: 99%

Mitochondrial biogenesis by NO yields functionally active mitochondria in mammals

Nisoli

Falcone

Tonello

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

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462

397

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“…It has been reported to have proapoptotic effects on epithelial cells (40) and macrophages (11,41). It also has been shown to have antiapoptotic activity by inactivating enzymes that mediate apoptosis, such as IL-1␤-converting enzyme, cysteine protease protein (42), caspases, and tissue-transglutaminase (43), or by inhibiting ceramide formation (44). In murine macrophages stimulated by LPS alone, induction of both iNOS and arginase II has been reported (12), and apoptosis is NO independent under these conditions (45).…”

Section: Discussionmentioning

confidence: 99%

Helicobacter pylori Induces Macrophage Apoptosis by Activation of Arginase II

Gobert

Cheng

Wang

et al. 2002

The Journal of Immunology

157

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Helicobacter pylori infection induces innate immune responses in macrophages, contributing to mucosal inflammation and damage. Macrophage apoptosis is important in the pathogenesis of mucosal infections but has not been studied with H. pylori. NO derived from inducible NO synthase (iNOS) can activate macrophage apoptosis. Arginase competes with iNOS by converting l-arginine to l-ornithine. Since we reported that H. pylori induces iNOS in macrophages, we now determined whether this bacterium induces arginase and the effect of this activation on apoptosis. NF-κB-dependent induction of arginase II, but not arginase I, was observed in RAW 264.7 macrophages cocultured with H. pylori. The time course of apoptosis matched those of both arginase and iNOS activities. Surprisingly, apoptosis was blocked by the arginase inhibitors Nω-hydroxy-l-arginine or Nω-hydroxy-nor-l-arginine, but not by the iNOS inhibitor N-iminoethyl-l-lysine. These findings were confirmed in peritoneal macrophages from iNOS-deficient mice and were not dependent on bacterial-macrophage contact. Ornithine decarboxylase (ODC), which metabolizes l-ornithine to polyamines, was also induced in H. pylori-stimulated macrophages. Apoptosis was abolished by inhibition of ODC and was restored by the polyamines spermidine and spermine. We also demonstrate that arginase II expression is up-regulated in both murine and human H. pylori gastritis tissues, indicating the likely in vivo relevance of our findings. Therefore, we describe arginase- and ODC-dependent macrophage apoptosis, which implicates polyamines in the pathophysiology of H. pylori infection.

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“…To assess the role of A-SMase in LPS-induced ceramide generation, we used a panel of structurally unrelated inhibitory compounds. To inhibit A-SMase, we used imipramine, which induces proteolysis of the enzyme (31,(33)(34)(35), and D609, which inhibits the phosphatidylcholine-specific phospholipase C, an enzyme known to be involved in A-SMase activation by LPS and other stimuli through generation of diacylglycerol (22,23,31,33,39,43). As controls of specificity we used scyphostatin and manumycin A, which are inhibitors of the neutral SMase (39,44,45).…”

Section: Lps Activates A-smase and Generates Ceramide In Immature Hummentioning

confidence: 99%

“…The conditions and concentrations of use of the various compounds interfering with the SMase/ceramide and NO signaling pathways have been described in detail previously (31,33,36,37,39). In brief, cell incubations with D609, manumycin A, scyphostatin, DETA-NO, 8 Br-cGMP, ODQ, KT5823, C2 ceramide, and exogenous A-SMase were performed for 10 min and those with imipramine for 1 h before LPS or E. coli administration.…”

Section: Pharmacological Treatmentsmentioning

confidence: 99%

Activation of Acid Sphingomyelinase and Its Inhibition by the Nitric Oxide/Cyclic Guanosine 3′,5′-Monophosphate Pathway: Key Events in Escherichia coli-Elicited Apoptosis of Dendritic Cells

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Perrotta

Palma

et al. 2004

The Journal of Immunology

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Depletion of dendritic cells (DCs) via apoptosis contributes to sepsis-induced immune suppression. The mechanisms leading to DC apoptosis during sepsis are not known. In this study we report that immature DCs undergo apoptosis when treated with high numbers of Escherichia coli. This effect was mimicked by high concentrations of LPS. Apoptosis was accompanied by generation of ceramide through activation of acid sphingomyelinase (A-SMase), was prevented by inhibitors of this enzyme, and was restored by exogenous ceramide. Compared with immature DCs, mature DCs expressed significantly reduced levels of A-SMase, did not generate ceramide in response to E. coli or LPS, and were insensitive to E. coli- and LPS-triggered apoptosis. However, sensitivity to apoptosis was restored by addition of exogenous A-SMase or ceramide. Furthermore, inhibition of A-SMase activation and ceramide generation was found to be the mechanism through which the immune-modulating messenger NO protects immature DCs from the apoptogenic effects of E. coli and LPS. NO acted through formation of cGMP and stimulation of the cGMP-dependent protein kinase. The relevance of A-SMase and its inhibition by NO/cGMP were confirmed in a mouse model of LPS-induced sepsis. DC apoptosis was significantly higher in inducible NO synthase-deficient mice than in wild-type animals and was significantly reduced by treatment ex vivo with NO, cGMP, or the A-SMase inhibitor imipramine. Thus, A-SMase plays a central role in E. coli/LPS-induced DC apoptosis and its inhibition by NO, and it might be a target of new therapeutic approaches to sepsis.

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Nitric oxide inhibits tumor necrosis factor-α-induced apoptosis by reducing the generation of ceramide

Cited by 103 publications

References 38 publications

Mitochondrial biogenesis by NO yields functionally active mitochondria in mammals

Mitochondrial biogenesis by NO yields functionally active mitochondria in mammals

Helicobacter pylori Induces Macrophage Apoptosis by Activation of Arginase II

Activation of Acid Sphingomyelinase and Its Inhibition by the Nitric Oxide/Cyclic Guanosine 3′,5′-Monophosphate Pathway: Key Events in Escherichia coli-Elicited Apoptosis of Dendritic Cells

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