Mycophenolic Acid, an Inhibitor of Imp Dehydrogenase That Is Also an Immunosuppressive Agent, Suppresses the Cytokine-Induced Nitric Oxide Production in Mouse and Rat Vascular Endothelial Cells

Senda, Mototaka; DeLustro, Barbara; Eugui, Elsie M.; Natsumeda, Yutaka

doi:10.1097/00007890-199511270-00015

Cited by 78 publications

(41 citation statements)

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“…To get closer to the in vivo situation it will be interesting to study the binding of peripheral mononuclear cells and granulocytes to MMpretreated TNFa-activated EC. Furthermore, we demonstrated, that GTP depletion induced by inhibition of IMPDH cannot account for MPA-mediated increase of VCAM-1 and E-selectin expression in TNFa-activated EC, since addition of guanosine, which acts as a salvage pathway precursor for GTP synthesis (Senda et al, 1995), did not prevent the e ect of MPA on CAMs (see Figure 5). …”

Section: Discussionmentioning

confidence: 88%

“…Preincubation with guanosine does not prevent the increased expression of VCAM-1 and E-selectin induced by MPA in TNFa-activated EC To determine whether the inhibition of inosine-5'-monophosphate dehydrogenase (IMPDH) is responsible for the increased expression of VCAM-1 and E-selectin induced by MPA in TNFa-activated EC, EC were preincubated in the presence or absence of 10 mM MPA with 300 mM guanosine for 24 h and cells were activated with TNFa (5 ng ml 71 ) for an additional 12 h. In a recent study, guanosine treatment has been shown to prevent MPA-mediated suppression of cytokine-induced nitric oxide production in rodent vascular endothelial cells (Senda et al, 1995). The e ect of guanosine was explained by its action as a salvage pathway precursor for GTP biosynthesis.…”

Section: Increased Adhesion Of U937 Cells To Tnfa-treated Human Ec Bymentioning

confidence: 99%

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Effect of mycophenolic acid on TNFα‐induced expression of cell adhesion molecules in human venous endothelial cells in vitro

Hauser

Johnson

Thévenod

et al. 1997

British J Pharmacology

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Mycophenolic acid (MPA) is an inhibitor of inosine‐5′‐monophosphate dehydrogenase and therefore interferes with cellular GTP biosynthesis. Recently, MPA has been used as an antiproliferative and immunosuppressive agent. In the present study, the effect of MPA on the expression of the endothelial cell adhesion molecules (CAMs), intercellular (I) CAM‐1, vascular (V) CAM‐1 and endothelial (E)‐selectin, was investigated in tumour necrosis factor‐α (TNFα)‐activated cultured human venous endothelial cells (EC). Surface expression of CAMs was measured by flow cytometry and mRNA expression by Northern blot analysis. Transcriptional activation of CAMs by the nuclear factor NF‐κB was determined by an electromobility shift assay. The function of CAMs was studied by a static adhesion assay with human monocyte‐like undifferentiated U937 cells. Pretreatment of TNFα‐ (5 ng ml−1, 12 h) activated EC with MPA (10 μM, 24 h) increased the binding of U937 cells, which had not been treated with MPA, by ∼amp;2 fold. MPA‐pretreatment of EC did not affect TNFα‐induced surface expression of ICAM‐1. However, VCAM‐1 and E‐selectin were increased 2–3 fold and remained elevated up to 24 h, by which time TNFα‐activated control EC had returned to baseline levels of expression. The effect of MPA on the surface expression of CAMs was half‐maximal at ∼amp;1 μM and required 12 h of pretreatment. Guanosine (0.3 mM), a precursor of GTP, did not prevent the effect of MPA on the expression of CAMs in TNFα‐activated EC. Kinetics of mRNA expression of CAMs mirrored protein expression: mRNA for ICAM‐1 was unaffected, whereas TNFα‐induced mRNA expression for E‐selectin and VCAM‐1 was prolonged and increased by MPA. This effect was not due to increased transcription mediated by the nuclear transcription factor NF‐κB. However, half‐life for E‐selectin mRNA was increased 10 fold by MPA, whereas ICAM‐1 mRNA half‐life was unchanged. The data demonstrate that apart from its antiproliferative effects on lymphocytes, MPA enhances TNFα‐induced VCAM‐1 and E‐selectin surface expression on EC by selectively increasing the mRNA‐stability of these cell adhesion molecules. This effect of MPA on EC appears to be independent from inhibition of inosine‐5′‐monophosphate dehydrogenase.

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Section: Discussionmentioning

confidence: 88%

Section: Increased Adhesion Of U937 Cells To Tnfa-treated Human Ec Bymentioning

confidence: 99%

Effect of mycophenolic acid on TNFα‐induced expression of cell adhesion molecules in human venous endothelial cells in vitro

Hauser

Johnson

Thévenod

et al. 1997

British J Pharmacology

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“…It impedes endothelial migration, proliferation and angiogenesis in vitro (21). In addition, MPA reduces endothelin-1 (ET-1) expression (22) and increases prostacyclin (PGI 2 ) release (23); it suppresses the cytokine-induced production of nitric oxide (NO) (24), presumably because of lack of GTP-derived tetrahydrobiopterin, essential coenzyme of the inducible NO synthetase (iNOS). Moreover, MPA (1-10 µM) inhibits superoxide anion production by endothelial NADPH-oxidase (Nox), since GTP depletion leads to the inactivation of Rac1, a G-protein involved in Nox activity (25).…”

Section: Effects On Endothelial Cellsmentioning

confidence: 99%

Mycophenolic acid in Rheumatology: mechanisms of action and severe adverse events

Zizzo¹,

Santis²,

Ferraccioli³

2011

Reumatismo

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MPA is clinically administered as morfolinoethyl ester (mycophenolate mofetil, MMF) or, more recently, as a salt (enteric-coated mycophenolate sodium). It is a fermentation product of Penicillium brevicompactum and other analogue fungi, identified by Gosio in 1893 as a weak antibacterial agent; in 1969 Franklin and Cook discovered its capacity to inhibit the inosine mono phosphate dehydrogenase (IMPDH), an enzyme involved in purine nucleotide synthesis (1)..

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“…Этим путем достигается блокада про-лиферации Т-и В-лимфоцитов и тем самым пода-вление продукции антител и генерации цитотокси-ческих клеток [50]. Существуют экспериментальные данные, говорящие о ренопротективном влиянии мофетила микофенолата за счет подавления цитоки-ниндуцирующей продукции NO и снижения проли-ферации гломерулярного и тубулярного матрикса [51]. В литературе имеются сведения о целесообразности перевода больных с лечения циклоспорином А в слу-чае развития нефротоксичности на мофетила мико-фенолат, что сопровождается улучшением почечных функций [52,53].…”

Section: обзоры литературыunclassified

Nephrotic Syndrome: Past, Present and Future

Ignatova¹,

Длин²

2017

Ross. vestn. perinatol. pediatr.

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Mycophenolic Acid, an Inhibitor of Imp Dehydrogenase That Is Also an Immunosuppressive Agent, Suppresses the Cytokine-Induced Nitric Oxide Production in Mouse and Rat Vascular Endothelial Cells

Cited by 78 publications

References 0 publications

Effect of mycophenolic acid on TNFα‐induced expression of cell adhesion molecules in human venous endothelial cells in vitro

Effect of mycophenolic acid on TNFα‐induced expression of cell adhesion molecules in human venous endothelial cells in vitro

Mycophenolic acid in Rheumatology: mechanisms of action and severe adverse events

Nephrotic Syndrome: Past, Present and Future

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