Inhibition of endothelial receptor expression and of T-cell ligand activity by mycophenolate mofetil

Blaheta, Roman A.; Leckel, Kerstin; Wittig, B.; Zenker, Dietmar; Oppermann, Elsie; Harder, Sebastian; Scholz, Martin; Weber, Stephan; Schuldes, H.; Encke, A.; Markus, B. H.

doi:10.1016/s0966-3274(98)80015-4

Cited by 53 publications

(30 citation statements)

References 17 publications

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“…The plasma levels obtained with a single dose of the IMPDH inhibitor MPA (Weigel et al, 2001) are comparable with the concentrations used in this series of in vitro experiments. However, because MPA is thought to inhibit leukocyte adhesion to the endothelium Blaheta et al, 1998), this in vitro effect is an apparent paradox. The upregulation of ICAM-1 by MPA was prevented by replenishing intracellular GTP pools by high doses (100 M) of guanine via the salvage pathway.…”

Section: Discussionmentioning

confidence: 99%

Depletion of Intracellular GTP Results in Nuclear Factor-κB Activation and Intercellular Adhesion Molecule-1 Expression in Human Endothelial Cells

2002

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The expression of the intercellular adhesion molecule 1 (ICAM-1) on the surface of endothelial cells plays an important role in immune-mediated processes. The induction by the proinflammatory cytokine interleukin (IL)-1␤ is regulated by nuclear transcription factor B (NF-B). We studied the effect of an inosine-5Ј-monophosphate dehydrogenase (IMPDH) inhibitor, mycophenolic acid (MPA), on constitutive and IL-1␤-induced expression of ICAM-1 in human umbilical vein endothelial cells (HUVECs). Unexpectedly, pretreatment with MPA enhanced the constitutive expression and potentiated the induction of ICAM-1 by IL-1␤, as detected by flow cytometry. Northern blot analysis revealed an increase in ICAM-1 mRNA levels in cells treated with MPA. This was associated with an increase in phosphorylation of IB-␣ (an inhibitor of NF-B), nuclear translocation of the NF-B subunits p50 and p65 and their binding to DNA as detected by Western blotting, confocal microscopy, and electrophoretic mobility shift assay. The upregulation of ICAM-1 by MPA was prevented by high doses (100 M) of guanine or guanosine but not by physiological doses (0.1 M), indicating that guanylates are involved in endothelial responses to IL-1␤. Cultivation of HUVECs in the absence of guanine enhanced further ICAM-1 expression during IMPDH inhibition. These results demonstrate that cytokinemediated endothelial ICAM-1 expression can be modulated by IMPDH inhibition. We believe this represents a novel interaction between endothelial guanylate metabolism, NF-B activation, and adhesion molecule expression.

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Section: Discussionmentioning

confidence: 99%

Depletion of Intracellular GTP Results in Nuclear Factor-κB Activation and Intercellular Adhesion Molecule-1 Expression in Human Endothelial Cells

2002

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“…MMF may also inhibit the proliferation of monocytes (54) and fibroblasts (4) and induce apoptosis of monocytes (12). In addition, MPA may inhibit the glycosylation and, consequently, the affinity of adhesion molecules expressed by lymphocytes and endothelial cells (6,32,65), again as a result of intracellular GTP depletion, thus limiting lymphocyte migration into the renal tissue. Therefore, MPA affects several crucial aspects of the inflammatory response, as will be discussed below.…”

Section: Mechanism Of Action Of Mpamentioning

confidence: 99%

Experimental and clinical rationale for use of MMF in nontransplant progressive nephropathies

Zatz

Noronha

Fujihara

2002

American Journal of Physiology-Renal Physiology

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The incidence of progressive nephropathies and, consequently, the population suffering from end-stage renal disease have increased steadily in recent years, posing an ever-growing cost, in both human and financial terms, to society. There is mounting evidence that, in both immune-mediated and nonimmune-mediated chronic nephropathies, renal inflammatory events are key to the propagation and perpetuation of renal injury. Mycophenolate mofetil (MMF) is an antilymphocyte agent recently introduced in clinical practice for the prevention of allograft rejection. The present review discusses clinical and experimental evidence that the anti-inflammatory action of MMF can be advantageously used to arrest immune- and nonimmune-mediated progressive injury of native kidneys as well.

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“…MMF operates through reduction of intracellular purine synthesis in both B-and T-lymphocytes, leading to inhibition of lymphocyte proliferation. Moreover, MMF does not only augment apoptosis of lymphocytic and monocytic cell lines (Cohn et al, 1999) and reduces the levels of immunoglobulin isotypes M, G and A produced by polyclonal activated Blymphocytes (Eugui et al, 1991), it also inhibits glycosylation of adhesion molecules (Blaheta et al, 1998) and regulates the secretion of inflammatory and anti-inflammatory cytokines (Durez et al, 1999). Consequently, MMF acts as a pluripotent immunomodulator in numerous types of immunological diseases (Schneider-Gold et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

Immunosuppression of experimental autoimmune myasthenia gravis by mycophenolate mofetil

Janssen

Phernambucq

Martínez‐Martínez

et al. 2008

Journal of Neuroimmunology

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Currently used non-specific immunosuppressive drugs often require intervention in myasthenia gravis (MG) and clinical improvement varies widely. To analyze the therapeutic effect of mycophenolate mofetil (MMF) in experimental autoimmune MG (EAMG), rats were immunized with acetylcholine receptors (AChRs) and subsequently treated with MMF or vehicle. MMF treatment resulted in a significant suppression of anti-rat AChR antibody titers. Interestingly, no abnormalities of neuromuscular transmission and adverse side effects were detected in MMF-treated EAMG animals. Moreover, anti-rat AChR antibody titers correlated to an improvement of clinical outcome. In conclusion, our data suggest that MMF acts as a potent immunosuppressant drug in EAMG.

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Inhibition of endothelial receptor expression and of T-cell ligand activity by mycophenolate mofetil

Cited by 53 publications

References 17 publications

Depletion of Intracellular GTP Results in Nuclear Factor-κB Activation and Intercellular Adhesion Molecule-1 Expression in Human Endothelial Cells

Depletion of Intracellular GTP Results in Nuclear Factor-κB Activation and Intercellular Adhesion Molecule-1 Expression in Human Endothelial Cells

Experimental and clinical rationale for use of MMF in nontransplant progressive nephropathies

Immunosuppression of experimental autoimmune myasthenia gravis by mycophenolate mofetil

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