Abstract
Macrophage migration inhibitory factor (MIF) is a pro-inflammatory cytokine playing crucial role in immunity. MIF exerts a unique tautomerase enzymatic activity that has relevance concerning its multiple functions and its small molecule inhibitors have been proven to block its pro-inflammatory effects. Here we demonstrate that some of the E-2-arylmethylene-1-tetralones and their heteroanalogues efficiently bind to MIF’s active site and inhibit MIF tautomeric (enolase, ketolase activity) functions. A small set of the synthesised derivatives, namely compounds (4), (23), (24), (26) and (32), reduced inflammatory macrophage activation. Two of the selected compounds (24) and (26), however, markedly inhibited ROS and nitrite production, NF-κB activation, TNF-α, IL-6 and CCL-2 cytokine expression. Pre-treatment of mice with compound (24) exaggerated the hypothermic response to high dose of bacterial endotoxin. Our experiments suggest that tetralones and their derivatives inhibit MIF’s tautomeric functions and regulate macrophage activation and thermal changes in severe forms of systemic inflammation.
Highlights
Macrophage migration inhibitory factor (MIF) was the first representative of those polypeptide immune mediators that have been grouped later as “cytokines”[1,2]
We have focused on the group of cyclic a,b-unsaturated ketones to study their inhibitory effects towards the MIF tautomerase activity
As regards the mechanism of action of the test compounds, we suppose, to other authors, the importance of the N-terminal proline. The role of this basic amino acid in the mechanism of MIF was discussed by some researchers[75]
Summary
Macrophage migration inhibitory factor (MIF) was the first representative of those polypeptide immune mediators that have been grouped later as “cytokines”[1,2]. Since its description 50 years ago MIF has accumulated a bewildering variety of immune and nonimmune functions[3]. MIF has been considered to be a missing link between inflammation and tumorigenesis[4]. MIF structure shares no homology with other known cytokines. Its structural relatives are the mammalian enzyme, D-dopachrometautomerase (DDT)[5], and the prokaryotic enzymes: chorismate mutase, 5-carboxymethyl-2-hydroxymuconate-isomerase (CHMI), trans- and cis-3-chloroacrylic acid dehalogenase (CaaD and cisCaaD, respectively), and 4-oxalocrotonate-tautomerase (4-OT)[6,7]. MIF exists in a homotrimeric form of 12.4 kD monomers. There are reports, of the occurrence of a dimeric form of MIF9 as well as of other oligomerisation states[10] and of heteromers[11]
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