Mizoribine Inhibits Production of Pro-inflammatory Cytokines and PGE2 in Macrophages

ABSTRACT

BACKGROUND: Mizoribine (MZR) is an imidazole nucleoside isolated from Eupenicillium brefeldianum. MZR is currently in clinical use for patients who have undergone renal transplantation. Therapeutic efficacy of MZR has also been demonstrated in rheumatoid arthritis and lupus nephritis. MZR has been shown to inhibit the proliferation of lymphocytes by interfering with inosine monophosphate dehydrogenase. Since the exact mechanism by which MZR benefits rheumatoid arthritis (RA) is not clear, we investigated the ability of MZR to direct its immunosuppressive influences on other antigen presenting cells, such as macrophages. METHODS: Mouse macrophage RAW264.7 cells were stimulated with lipopolysaccharide in the presence of MZR. To elucidate the mechanism of the therapeutic efficacy in chronic inflammatory diseases, we examined the effects of MZR on the production of pro-inflammatory cytokines, nitric oxide (NO) and prostaglandin E2 (PGE2) in macrophages. RESULTS: MZR dose-dependently decreased the production of nitric oxide and pro- inflammatory cytokines such as tumor necrosis factor-alpha (TNF-alpha), interleukins 1beta (IL-beta) and IL-6 PGE2. Examination of gene expression levels showed that the anti-inflammatory effect correlated with the down-regulation of inducible nitiric oxide synthase expression, cycloxygenase-2 expression and TNF-alpha gene expression. CONCLUSION: In this work, we resulted whether MZR (1.25~10 microgram/ml) inhibited macrophage activation by inhibiting secretion of pro-inflammatory cytokines, NO and PGE2. These findings provide an explanation for the therapeutic efficacy of MZR in chronic inflammation- associated diseases.