ISO-1 binding to the tautomerase active site of MIF inhibits its pro-inflammatory activity and increases survival in severe sepsis
ISO-1 binding to the tautomerase active site of MIF inhibits its pro-inflammatory activity and increases survival in severe sepsis
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DOI：
10.1074/jbc.c500243200
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发表时间：
2005-11-04
影响因子：
4.8
通讯作者：
Tracey, KJ
中科院分区：
文献类型：
--
作者：
Al-Abed, Y;Dabideen, D;Tracey, KJ
MIF是一种促炎性细胞因子，与脓毒症、关节炎和其他炎性疾病的发病机制有关。针对MIF的抗体在炎症的实验模型中是有效的，并且对抑制其有害的细胞因子活性的策略感兴趣。在这里，我们确定了一种机制，抑制MIF促炎活性的目标MIF互变异构酶活性。我们设计了小分子来抑制这种互变异构酶活性;先导分子“ISO-1（（S，R）3-（4-羟基苯基）-4，5-二氢-5-异恶唑乙酸甲酯）”在体外显著抑制细胞因子活性。此外，ISO-1抑制从LPS处理的野生型小鼠分离的巨噬细胞释放肿瘤坏死因子，但对MIF缺陷型巨噬细胞释放细胞因子没有影响。ISO-1抑制MIF的治疗重要性通过在临床相关时间范围内对盲肠结扎和穿刺诱导的脓毒症的显著保护来证明。这些结果将ISO-1鉴定为具有治疗意义的MIF促炎活性的第一个小分子抑制剂，并表明MIF活性位点作为人类脓毒症治疗干预的新靶点的潜力。
MIF is a proinflammatory cytokine that has been implicated in the pathogenesis of sepsis, arthritis, and other inflammatory diseases. Antibodies against MIF are effective in experimental models of inflammation, and there is interest in strategies to inhibit its deleterious cytokine activities. Here we identify a mechanism of inhibiting MIF pro-inflammatory activities by targeting MIF tautomerase activity. We designed small molecules to inhibit this tautomerase activity; a lead molecule, "ISO-1 (( S, R)3-( 4-hydroxyphenyl)-4,5-dihydro-5-isoxazole acetic acid methyl ester)," significantly inhibits the cytokine activity in vitro. Moreover, ISO-1 inhibits tumor necrosis factor release from macrophages isolated from LPS-treated wild type mice but has no effect on cytokine release from MIF-deficient macrophages. The therapeutic importance of the MIF inhibition by ISO-1 is demonstrated by the significant protection from sepsis, induced by cecal ligation and puncture in a clinically relevant time frame. These results identify ISO-1 as the first small molecule inhibitor of MIF proinflammatory activities with therapeutic implications and indicate the potential of the MIF active site as a novel target for therapeutic interventions in human sepsis.