Nitric Oxide Regulates Immune Cell Bioenergetic: A Mechanism to Understand Immunomodulatory Functions of Nitric Oxide-Releasing Anti-Inflammatory Drugs

Fiorucci, Stefano; Mencarelli, Andrea; Distrutti, Eleonora; Baldoni, Monia; Soldato, Piero Del; Morelli, Antonio

doi:10.4049/jimmunol.173.2.874

Cited by 32 publications

(21 citation statements)

References 50 publications

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“…In any event, the result is greater bioavailability of iNO at physO 2 . Artificially raising iNO levels by addition of iNO donors to cell cultures maintained at atmosO 2 has been shown to inhibit cell proliferation (16,23) and promote cell death (24). Thus, the decreased proliferation in the CD3/CD28-stimulated cultures at physO 2 can be expected on the basis of the increased iNO and likely reflects the appropriate functioning of iNO an immunomodulatory molecule with a function that is largely lost in cultures maintained at atmosO 2 .…”

Section: Discussionmentioning

confidence: 99%

Importance of culturing primary lymphocytes at physiological oxygen levels

Atkuri

Herzenberg²,

Niemi³

et al. 2007

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

151

132

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Although studies with primary lymphocytes are almost always conducted in CO 2 incubators maintained at atmospheric oxygen levels (atmosO 2 ; 20%), the physiological oxygen levels (physO 2 ; 5%) that cells encounter in vivo are 2-4 times lower. We show here that culturing primary T cells at atmosO 2 significantly alters the intracellular redox state (decreases intracellular glutathione, increases oxidized intracellular glutathione), whereas culturing at physO2 maintains the intracellular redox environment (intracellular glutathione/oxidized intracellular glutathione) close to its in vivo status. Furthermore, we show that CD3/CD28-induced T cell proliferation (based on proliferation index and cell yield) is higher at atmosO2 than at physO2. This apparently paradoxical finding, we suggest, may be explained by two additional findings with CD3/CD28-stimulated T cells: (i) the intracellular NO (iNO) levels are higher at physO2 than at atmosO2; and (ii) the peak expression of CD69 is significantly delayed and more sustained at physO2 that at atmosO2. Because high levels of intracellular NO and sustained CD69 tend to down-regulate T cell responses in vivo, the lower proliferative T cell responses at physO2 likely reflect the in vitro operation of the natural in vivo regulatory mechanisms. Thus, we suggest caution in culturing primary lymphocytes at atmosO2 because the requisite adaptation to nonphysiological oxygen levels may seriously skew T cell responses, particularly after several days in culture.glutathione ͉ low oxygen ͉ nitric oxide ͉ proliferation

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Section: Discussionmentioning

confidence: 99%

Importance of culturing primary lymphocytes at physiological oxygen levels

Atkuri

Herzenberg²,

Niemi³

et al. 2007

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

151

132

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“…The culture medium was replaced every 48 h with DMEM containing 5 g/ml insulin. Glucose uptake was measured as described previously (Fiorucci et al, 2004). In brief, fully differentiated adipocytes were starved overnight and then incubated with for 18 h at 37°C in glucose uptake buffer (8.1 mM Na 2 HPO 4 , 1.4 mM KH 2 PO 4 , 2.6 mM KCl, 136 mM NaCl, 0.5 mM MgCl 2 , 0.9 mM CaCl 2 , pH 7.4).…”

Section: Methodsmentioning

confidence: 99%

The Farnesoid X Receptor Promotes Adipocyte Differentiation and Regulates Adipose Cell Function in Vivo

Rizzo

Disante²,

Mencarelli³

et al. 2006

Mol Pharmacol

Self Cite

141

138

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The differentiation of a preadipocyte into a mature adipocyte is a highly regulated process that requires a scripted program of transcriptional events leading to changes in gene expression. Several genes are associated with adipogenesis, including the CAAT/enhancer-binding protein (C/EBPs) and peroxisome proliferator-activated receptor (PPAR) families of transcription factors. In this study, we have investigated the role of the farnesoid X receptor (FXR), a bile acid-activated nuclear receptor, in regulating adipogenesis in a preadipocyte cell line (3T3-L1 cells). Our results show that FXR is expressed in the white adipose tissue of adult mice and in differentiated 3T3-L1 cells but not in undifferentiated preadipocytes. Exposure of 3T3-L1 cells to INT-747 (6-ethyl cheno-deoxycholic acid), a potent and selective FXR ligand, increases preadipocyte differentiation induced by a differentiating mixture containing insulin. Augmentation of differentiating mixture-induced differentiation of 3T3-L1 cells by INT-747 associated with induction of aP2, C/EBP␣, and PPAR␥2 mRNAs along with other adipocyterelated genes. This effect was reversed by guggulsterone, an FXR antagonist, and partially reverted by GW9662 (2-chloro-5-nitro-N-phenylbenzamide), a selective PPAR␥ antagonist, indicating that FXR modulates adipocyte-related genes by PPAR␥-dependent and -independent pathways. Regulation of adipocyte-related genes by INT-747 was lost in FXRϪ/Ϫ mice, indicating that modulation of these genes by INT-747 requires an intact FXR. In addition, INT-747 enhances both insulininduced serine phosphorylation of Akt and glucose uptake by 3T3-L1 cells. Taken together, these results suggest that activation of FXR plays a critical role in regulating adipogenesis and insulin signaling.

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“…A good candidate to make the link between defective RCC function and apoptosis are ROS, as they are often formed when RCCs are partially inhibited. These ROS, which can also be generated in physiological conditions, are (Clementi et al, 1998;Fiorucci et al, 2004) (3) Ceramide synthesis: or depending on cancer type (Ryland et al, 2011) Direct RCC III inhibition and subsequent ROS production (Gudz et al, 1997;Di Paola et al, 2000) Abbreviations: NO, nitric oxide; O 2 , oxygen; RCC, respiratory chain complex; ROS, reactive oxygen species.…”

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confidence: 99%

Mitochondrial respiratory chain complexes: apoptosis sensors mutated in cancer?

2011

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Mutations in cancer cells affecting subunits of the respiratory chain (RC) indicate a central role of oxidative phosphorylation for tumourigenesis. Recent studies have suggested that such mutations of RC complexes impact apoptosis induction. We review here the evidence for this hypothesis, which in particular emerged from work on how complex I and II mediate signals for apoptosis. Both protein aggregates are specifically inhibited for apoptosis induction through different means by exploiting with protease activation and pH change, two widespread but independent features of dying cells. Nevertheless, both converge on forming reactive oxygen species for the demise of the cell. Investigations into these mitochondrial processes will remain a rewarding area for unravelling the causes of tumourigenesis and for discovering interference options.

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Nitric Oxide Regulates Immune Cell Bioenergetic: A Mechanism to Understand Immunomodulatory Functions of Nitric Oxide-Releasing Anti-Inflammatory Drugs

Cited by 32 publications

References 50 publications

Importance of culturing primary lymphocytes at physiological oxygen levels

Importance of culturing primary lymphocytes at physiological oxygen levels

The Farnesoid X Receptor Promotes Adipocyte Differentiation and Regulates Adipose Cell Function in Vivo

Mitochondrial respiratory chain complexes: apoptosis sensors mutated in cancer?

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