Guanine ribonucleotide depletion inhibits T cell activation. Mechanism of action of the immunosuppressive drug mizoribine.

Turka, Laurence A.; Dayton, J. D.; Sinclair, Graham; Thompson, Craig B.; Mitchell, Beverly S.

doi:10.1172/jci115101

Cited by 143 publications

(74 citation statements)

References 40 publications

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“…results in the depletion of the intracellular guanine nucleotide. The depletion of the guanine nucleotide causes G i/s blockage in human T cells (12). Although immunophilins have been investigated for immunosuppressants cyclosporin A, FK506, rapamycin, and deoxyspergualin, immunophilin specific for mizoribine has not yet been investigated.…”

Section: Discussionmentioning

confidence: 99%

“…The mechanisms of the immunosuppressive effects of mizoribine demonstrated that mizoribine is phosphorylated by adenosine kinase (10), and the monophosphate inhibits from IMP dehydrogenase (10) or both IMP dehydrogenase and GMP synthase (11). The inhibition of the enzymes results in the depletion of intracellular guanine nucleotides as shown in both murine and human systems (12).…”

mentioning

confidence: 99%

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Mammalian HSP60 Is a Major Target for an Immunosuppressant Mizoribine

Itoh¹,

Komatsuda²,

Wakui³

et al. 1999

Journal of Biological Chemistry

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It has been reported that immunosuppressant cyclosporin A or FK506 binds to immunophilins in the cell and that these immunophilins make a complex with molecular chaperones HSP70 or HSP90. Although mizoribine has been used clinically as an immunosuppressant, immunophilins of the agent have not yet been fully understood. We investigated their specific binding proteins using mizoribine affinity column chromatography and porcine kidney cytosols. By increasing mizoribine in the eluant from the column, two major proteins (with molecular masses of 60 and 43 kDa) were detected by SDSpolyacrylamide gel electrophoresis. Based on the amino acid sequence analysis of these proteins, 60-and 43-kDa mizoribine-binding proteins were identified with HSP60 and cytosolic actin, respectively. A considerable amount of actin was also eluted from the affinity column by nucleotides, but a very low quantity of HSP60 was eluted under the same conditions. On the other hand, HSP60 was eluted as a major protein in the eluant that was eluted preferentially, with nucleotide followed by mizoribine. Actin was also detected in the eluant, but the quantity of the protein was very low. These results indicated that HSP60 has high affinity to mizoribine, and the interaction was also observed on surface plasmon resonance analysis. Although HSP60 or GroE facilitated refolding of citrate synthase in vitro, mizoribine interfered with the chaperone activity of HSP60. On different types of mizoribine affinity columns, HSP60 or actin recognized the NH 2 group of mizoribine, and this group may be a functional group of the agent.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Mammalian HSP60 Is a Major Target for an Immunosuppressant Mizoribine

Itoh¹,

Komatsuda²,

Wakui³

et al. 1999

Journal of Biological Chemistry

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“…This enzyme is strongly expressed in activated T and B cells (11). The antiproliferative effect of mycophenolate acid on T cells was clearly demonstrated in vitro (7,8,12,13). Methotrexate (MTX) is a folate antagonist that blocks dihydrofolate reductase and TS (14), but it can also block the first step of purine biosynthesis (15).…”

Section: Restriction Of De Novo Nucleotide Biosynthesis Interferes Wimentioning

confidence: 99%

Restriction of De Novo Nucleotide Biosynthesis Interferes with Clonal Expansion and Differentiation into Effector and Memory CD8 T Cells

Quéméneur

Beloeil

Michallet

et al. 2004

The Journal of Immunology

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Nucleotide synthesis inhibitors are currently used in neoplastic diseases or as immunosuppressive agents for the prevention of acute rejection in organ transplantation and the treatment of autoimmune disorders. We have previously described that these inhibitors interfere with proliferation and survival of primary T cells in vitro. However, the precise effects of nucleotide restriction on effector and memory functions have not been elucidated. In this study, we investigated the impact of nucleotide synthesis inhibition on CD8 T cell differentiation by using TCR transgenic mice (F5) specific for the influenza virus nucleoprotein 68 peptide presented on the H-2Db molecule. Our results show that methotrexate and 5-fluorouracil prevent the acquisition of effector functions, such as IFN-γ, granzyme B expression, and cytotoxic function following antigenic stimulation of naive cells. Surprisingly, in the presence of mycophenolate mofetil, activated F5 cells are still able to produce granzyme B and to kill target cells but to a lesser extent compared with control. All three inhibitors interfere with the differentiation of naive cells into memory CD8 T cells. In contrast, the drugs are unable to inhibit the development of improved cytotoxic functions displayed by memory CD8 T cells.

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“…Downregulation of the CDK inhibitor p27 Kip1 was shown to depend on the binding of IL-2 to its high-affinity trimeric receptor (11)(12)(13). Earlier studies with the immunosuppressive agent mizoribine (MZB), another inhibitor of IMPDH, have shown that depletion of guanine nucleotides in T lymphocytes inhibits the entry into S phase of the cell cycle, but does not alter early G 1 events such as expression of c-Myc, IL-2, or IL-2R (14). Therefore, we investigated whether IMPDH inhibitors, including MPA, could affect T cell proliferation by interfering with IL-2-dependent signaling events that are required for p27 Kip1 degradation and progression to the S phase of the cell cycle.…”

Section: Ycophenolate Mofetil (Mmf)mentioning

confidence: 99%

Mycophenolic Acid Inhibits IL-2-Dependent T Cell Proliferation, But Not IL-2-Dependent Survival and Sensitization to Apoptosis

Quéméneur¹,

Flacher²,

Gerland

et al. 2002

The Journal of Immunology

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Mycophenolic acid (MPA), the active metabolite of the immunosuppressive drug mycophenolate mofetil, is a selective inhibitor of inosine 5′-monophosphate dehydrogenase type II, a de novo purine nucleotide synthesis enzyme expressed in T and B lymphocytes and up-regulated upon cell activation. In this study, we report that the blockade of guanosine nucleotide synthesis by MPA inhibits mitogen-induced proliferation of PBL, an effect fully reversed by addition of guanosine and shared with mizoribine, another inhibitor of inosine 5′-monophosphate dehydrogenase. Because MPA does not inhibit early TCR-mediated activation events, such as CD25 expression and IL-2 synthesis, we investigated how it interferes with cytokine-dependent proliferation and survival. In activated lymphoblasts that are dependent on IL-2 or IL-15 for their proliferation, MPA does not impair signaling events such as of the extracellular signal-regulated kinase 2 and Stat5 phosphorylation, but inhibits down-regulation of the cyclin-dependent kinase inhibitor p27Kip1. Therefore, in activated lymphoblasts, MPA specifically interferes with cytokine-dependent signals that control cell cycle and blocks activated T cells in the mid-G1 phase of the cell cycle. Although it blocks IL-2-mediated proliferation, MPA does not inhibit cell survival and Bcl-xL up-regulation by IL-2 or other cytokines whose receptors share the common γ-chain (CD132). Finally, MPA does not interfere with IL-2-dependent acquisition of susceptibility to CD95-mediated apoptosis and degradation of cellular FLIP. Therefore, MPA has unique functional properties not shared by other immunosuppressive drugs interfering with IL-2R signaling events such as rapamycin and CD25 mAbs.

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Guanine ribonucleotide depletion inhibits T cell activation. Mechanism of action of the immunosuppressive drug mizoribine.

Cited by 143 publications

References 40 publications

Mammalian HSP60 Is a Major Target for an Immunosuppressant Mizoribine

Mammalian HSP60 Is a Major Target for an Immunosuppressant Mizoribine

Restriction of De Novo Nucleotide Biosynthesis Interferes with Clonal Expansion and Differentiation into Effector and Memory CD8 T Cells

Mycophenolic Acid Inhibits IL-2-Dependent T Cell Proliferation, But Not IL-2-Dependent Survival and Sensitization to Apoptosis

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