Inhibitory effect of mizoribine on matrix metalloproteinase-1 production in synovial fibroblasts and THP-1 macrophages

Zhong, BinBin; Tajima, Masanori; Takahara, Hidenari; Nochi, Hiromi; Tamoto, Koichi; Tamura, Naoto; Kobayashi, Shigeto; Tamura, Yasuaki; Ikeda, Makoto; Akimoto, Tomohiro

doi:10.3109/s10165-005-0406-x

Cited by 4 publications

(3 citation statements)

References 17 publications

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“…The ability of Miz treatment to reduce the number of activated macrophages in patients with IgAN could be due to an indirect effect of suppressing T cell-mediated recruitment and activation of macrophages. Alternatively, this could be due to a direct effect of the drug on macrophage function, a possibility supported by experimental studies showing that Miz treatment can ameliorate interstitial fibrosis by preventing macrophage accumulation [11,12], and that Miz can exert direct effects on macrophage function in vitro [13].…”

Section: Discussionmentioning

confidence: 98%

Use of mizoribine as a rescue drug for steroid-resistant pediatric IgA nephropathy

et al. 2008

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Recent clinical trials have shown a beneficial effect of mizoribine (Miz), an immunosuppressive drug, in the treatment of new-onset pediatric IgA nephropathy (IgAN). In this study, we evaluated the efficacy of Miz treatment in three children with established steroid-resistant IgAN. The patients had IgAN featuring persistent proteinuria and diffuse mesangial proliferation and had failed to respond to 2 years of treatment with prednisolone. Based upon the second biopsy results, patients were given methylprednisolone (mPSL) pulse therapy that induced a transient reduction in proteinuria, which was reversed when the mPSL dose was tapered. Miz therapy was then instigated in place of pulse mPSL. All three patients showed a substantial reduction in proteinuria and resolution of hematuria within 5 months. A follow-up biopsy in two of the patients showed a substantial reduction in the severity of glomerular lesions and a decrease in the number of activated macrophages. In conclusion, Miz therapy was found to be a safe and effective therapy in three cases of steroid-resistant pediatric IgAN. The ability of Miz to reduce the number of activated macrophages may be an important mechanism by which this drug ameliorated renal disease in these patients.

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Section: Discussionmentioning

confidence: 98%

Use of mizoribine as a rescue drug for steroid-resistant pediatric IgA nephropathy

et al. 2008

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“…RA is characterized by synovial inflammation and the destruction of cartilage and bone (Zhong et al, 2005). The pathology of RA extends throughout the synovial joint and, in severe cases, involves many other organs.…”

Section: Introductionmentioning

confidence: 99%

Auranofin inhibits overproduction of pro-inflammatory cytokines, cyclooxygenase expression and PGE2 production in macrophages

Han

Kim

et al. 2008

Arch. Pharm. Res.

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Auranofin (AF), a gold compound, is an orally active therapeutic agent used to treat rheumatoid arthritis (RA), a self-perpetuating inflammatory disease. RA is characterized by autoimmune-mediated proliferation of synovial cells that leads to inflammation, pain, and swelling in most major joints: However, the mechanism as to how AF relieves RA symptoms has not been fully elucidated. The object of this study was to examine the ability of AF to immunomodulate macrophages as antigen presenting cells (APCs). Macrophages are recognized as playing an important role in the pathogenesis of RA, in that there is a relative abundance of macrophage-derived cytokines, such as tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta) and interleukin-6 (IL-6) in rheumatoid synovium. In this work, we tested whether AF (2.5-20 mM) could inhibit inflammatory activity in the macrophage cell line RAW 264.7. AF decreased production of nitric oxide (NO) and the pro-inflammatory cytokines, TNF-alpha, IL-1beta and IL-6 in macrophages. Furthermore, AF inhibited cyclooxygenase-2 (COX-2)-dependent prostaglandin E2 (PGE2) production in a concentration-dependent manner. In conclusion, these findings may provide an explanation for the clinical effects of AF in patients with RA.

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“…All cell lines treated with mizoribine showed a global reduction in reporter protein expression when compared with untreated cells. This expected effect is likely due to partial guanosine pool depletion induced by IMPDH inhibition [28,34,35]. Interestingly, the reduction in transcription and translation of the reporter was significantly less severe only in cells over-expression HCE-WT-HA for both mizoribine concentrations.…”

Section: Discussionmentioning

confidence: 93%

The Immunosuppressive Agent Mizoribine Monophosphate Is an Inhibitor of the Human RNA Capping Enzyme

et al. 2013

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Mizoribine monophosphate (MZP) is a specific inhibitor of the cellular inosine-5′-monophosphate dehydrogenase (IMPDH), the enzyme catalyzing the rate-limiting step of de novo guanine nucleotide biosynthesis. MZP is a highly potent antagonistic inhibitor of IMPDH that blocks the proliferation of T and B lymphocytes that use the de novo pathway of guanine nucleotide synthesis almost exclusively. In the present study, we investigated the ability of MZP to directly inhibit the human RNA capping enzyme (HCE), a protein harboring both RNA 5′-triphosphatase and RNA guanylyltransferase activities. HCE is involved in the synthesis of the cap structure found at the 5′ end of eukaryotic mRNAs, which is critical for the splicing of the cap-proximal intron, the transport of mRNAs from the nucleus to the cytoplasm, and for both the stability and translation of mRNAs. Our biochemical studies provide the first insight that MZP can inhibit the formation of the RNA cap structure catalyzed by HCE. In the presence of MZP, the RNA 5′-triphosphatase activity appears to be relatively unaffected while the RNA guanylyltransferase activity is inhibited, indicating that the RNA guanylyltransferase activity is the main target of MZP inhibition. Kinetic studies reveal that MZP is a non-competitive inhibitor that likely targets an allosteric site on HCE. Mizoribine also impairs mRNA capping in living cells, which could account for the global mechanism of action of this therapeutic agent. Together, our study clearly demonstrates that mizoribine monophosphate inhibits the human RNA guanylyltransferase in vitro and impair mRNA capping in cellulo.

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Inhibitory effect of mizoribine on matrix metalloproteinase-1 production in synovial fibroblasts and THP-1 macrophages

Cited by 4 publications

References 17 publications

Use of mizoribine as a rescue drug for steroid-resistant pediatric IgA nephropathy

Use of mizoribine as a rescue drug for steroid-resistant pediatric IgA nephropathy

Auranofin inhibits overproduction of pro-inflammatory cytokines, cyclooxygenase expression and PGE2 production in macrophages

The Immunosuppressive Agent Mizoribine Monophosphate Is an Inhibitor of the Human RNA Capping Enzyme

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