共 25 条
ISO-1 binding to the tautomerase active site of MIF inhibits its pro-inflammatory activity and increases survival in severe sepsis
被引:255
作者:
Al-Abed, Y
Dabideen, D
Aljabari, B
Valster, A
Messmer, D
Ochani, M
Tanovic, M
Ochani, K
Bacher, M
Nicoletti, F
Metz, C
Pavlov, VA
Miller, EJ
Tracey, KJ
机构:
[1] N Shore Long Isl Jewish Inst Med Res, Med Chem Lab, Manhasset, NY 11030 USA
[2] New York Sch Med, New York, NY 10016 USA
[3] N Shore Long Isl Jewish Inst Med Res, Ctr Oncol & Cell Biol, Manhasset, NY 11030 USA
[4] N Shore Long Isl Jewish Inst Med Res, Expt Immunol Lab, Manhasset, NY 11030 USA
[5] N Shore Long Isl Jewish Inst Med Res, Lab Biomed Sci, Manhasset, NY 11030 USA
[6] Univ Bonn, Dept Neurol, D-53105 Bonn, Germany
[7] Univ Catania, Dept Biomed Sci, I-95021 Catania, Italy
[8] N Shore Univ Hosp, N Shore Long Isl Jewish Inst Med Res, Med Biochem Lab, Manhasset, NY 11030 USA
[9] N Shore Univ Hosp, N Shore Long Isl Jewish Inst Med Res, Dept Surg, Manhasset, NY 11030 USA
关键词:
D O I:
10.1074/jbc.C500243200
中图分类号:
Q5 [生物化学];
Q7 [分子生物学];
学科分类号:
071010 ;
081704 ;
摘要:
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.
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页码:36541 / 36544
页数:4
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