title: Novel inhibitors of macrophage migration inhibitory factor prevent cytokine-induced beta cell death.
abstract: Macrophage migration inhibitory factor is a multifunctional cytokine involved in the regulation of immune processes and also in apoptosis induction. Elevated MIF expression is detrimental for insulin-producing beta cells and MIF inhibition protected beta cells from several cytotoxic insults such as inflammatory cytokines, high fatty acids or high glucose concentrations. Therefore, the aim of this study was to investigate two newly synthesized small molecule MIF inhibitors (K664-1 and K647-1) and to compare them with previously established effects of the prototypical MIF inhibitor, ISO-1. Our results indicate that K664-1 and K647-1 are 160- and 40-fold more effective in inhibition of MIF׳s tautomerase activity than ISO-1. Also, new inhibitors confer beta cell protection from cytokine-triggered apoptosis at significantly lower concentrations than ISO-1. Although all three MIF inhibitors inhibit caspase 3 activity, K664-1 and K647-1 suppress pro-apoptotic BAX protein expression and up-regulate anti-apoptotic Bcl-2 mRNA. Finally, all three MIF inhibitors operate through blockade of nitric oxide production stimulated by cytokines. In conclusion, two novel MIF inhibitors are more potent than ISO-1 and operate through inhibition of the mitochondria-related apoptotic pathway. We propose that these compounds represent a unique class of anti-MIF antagonists that should be further tested for therapeutic use.
authors: Department of Immunology, Institute for Biological Research "Sinisa Stankovic", University of Belgrade, Belgrade, Serbia.
authors: Milica
authors: M
authors: Vujicic
authors: Department of Immunology, Institute for Biological Research "Sinisa Stankovic", University of Belgrade, Belgrade, Serbia.
authors: Ivana
authors: I
authors: Nikolic
authors: Department of Immunology, Institute for Biological Research "Sinisa Stankovic", University of Belgrade, Belgrade, Serbia.
authors: Tamara
authors: T
authors: Krajnovic
authors: The Feinstein Institute for Medical Research, Manhasset, New York, USA.
authors: Kai-Fan
authors: KF
authors: Cheng
authors: The Feinstein Institute for Medical Research, Manhasset, New York, USA.
authors: Sonya
authors: S
authors: VanPatten
authors: The Feinstein Institute for Medical Research, Manhasset, New York, USA.
authors: Mingzhu
authors: M
authors: He
authors: Department of Immunology, Institute for Biological Research "Sinisa Stankovic", University of Belgrade, Belgrade, Serbia.
authors: Stanislava
authors: S
authors: Stosic-Grujicic
authors: Department of Immunology, Institute for Biological Research "Sinisa Stankovic", University of Belgrade, Belgrade, Serbia.
authors: Ivana
authors: I
authors: Stojanovic
authors: The Feinstein Institute for Medical Research, Manhasset, New York, USA. Electronic address: yalabed@nshs.edu.
authors: Yousef
authors: Y
authors: Al-Abed
authors: Department of Immunology, Institute for Biological Research "Sinisa Stankovic", University of Belgrade, Belgrade, Serbia. Electronic address: cvjetica@gmail.com.
authors: Tamara
authors: T
authors: Saksida
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism; D002396:Catechols / Q000494:pharmacology*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D006574:Heterocyclic Compounds, 2-Ring / Q000494:pharmacology*; D050417:Insulin-Secreting Cells / Q000187:drug effects*; D007371:Interferon-gamma / Q000494:pharmacology; D053583:Interleukin-1beta / Q000494:pharmacology; D019746:Intramolecular Oxidoreductases / Q000037:antagonists & inhibitors* / Q000235:genetics; D007555:Isoxazoles / Q000494:pharmacology; D008263:Macrophage Migration-Inhibitory Factors / Q000037:antagonists & inhibitors* / Q000235:genetics; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009525:Niacin / Q000031:analogs & derivatives* / Q000494:pharmacology; D010091:Oximes / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: C462499:3-(4-hydroxyphenyl)-4,5-dihydro-5-isoxazoleacetic acid methyl ester; D002396:Catechols; D006574:Heterocyclic Compounds, 2-Ring; D053583:Interleukin-1beta; D007555:Isoxazoles; C000602295:K647-1 compound; C000602296:K664-1 compound; D008263:Macrophage Migration-Inhibitory Factors; D010091:Oximes; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D009525:Niacin; D007371:Interferon-gamma; C505410:Casp3 protein, rat; D053148:Caspase 3; D019746:Intramolecular Oxidoreductases; C076231:Mif protein, mouse
keywords: Apoptosis; Cytokines; Diabetes; ISO-1; Macrophage migration inhibitory factor