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Eur J Pharmacol. 2014 Oct 5;740:683-9. doi: 10.1016/j.ejphar.2014.06.009. Epub 2014 Jun 23.

Novel inhibitors of macrophage migration inhibitory factor prevent cytokine-induced beta cell death.

Author information

1
Department of Immunology, Institute for Biological Research "Sinisa Stankovic", University of Belgrade, Belgrade, Serbia.
2
The Feinstein Institute for Medical Research, Manhasset, New York, USA.
3
The Feinstein Institute for Medical Research, Manhasset, New York, USA. Electronic address: yalabed@nshs.edu.
4
Department of Immunology, Institute for Biological Research "Sinisa Stankovic", University of Belgrade, Belgrade, Serbia. Electronic address: cvjetica@gmail.com.

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.

KEYWORDS:

Apoptosis; Cytokines; Diabetes; ISO-1; Macrophage migration inhibitory factor

PMID:
24967533
DOI:
10.1016/j.ejphar.2014.06.009
[Indexed for MEDLINE]

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