Selective Targeting of a Disease-Related Conformational Isoform of Macrophage Migration Inhibitory Factor Ameliorates Inflammatory Conditions.

Abstract

Macrophage migration inhibitory factor (MIF), a proinflammatory cytokine and counterregulator of glucocorticoids, is a potential therapeutic target. MIF is markedly different from other cytokines because it is constitutively expressed, stored in the cytoplasm, and present in the circulation of healthy subjects. Thus, the concept of targeting MIF for therapeutic intervention is challenging because of the need to neutralize a ubiquitous protein. In this article, we report that MIF occurs in two redox-dependent conformational isoforms. We show that one of the two isoforms of MIF, that is, oxidized MIF (oxMIF), is specifically recognized by three mAbs directed against MIF. Surprisingly, oxMIF is selectively expressed in the plasma and on the cell surface of immune cells of patients with different inflammatory diseases. In patients with acute infections or chronic inflammation, oxMIF expression correlated with inflammatory flare-ups. In addition, anti-oxMIF mAbs alleviated disease severity in mouse models of acute and chronic enterocolitis and improved, in synergy with glucocorticoids, renal function in a rat model of crescentic glomerulonephritis. We conclude that oxMIF represents the disease-related isoform of MIF; oxMIF is therefore a new diagnostic marker for inflammation and a relevant target for anti-inflammatory therapy.

• Authors: Michael Thiele, Randolf J Kerschbaumer, Frederick W K Tam, Dirk Völkel, Patrice Douillard, Alexander Schinagl, Harald Kühnel, Jennifer Smith, John P McDaid, Gurjeet Bhangal, Mei-Ching Yu, Charles D Pusey, H Terence Cook, Josef Kovarik, Erica Magelky, Atul Bhan, Manfred Rieger, Geert C Mudde, Hartmut Ehrlich, Bernd Jilma, Herbert Tilg, Alexander Moschen, Cox Terhorst, Friedrich Scheiflinger
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 195 Issue 5 Pg. 2343-52 (Sep 01 2015) ISSN: 1550-6606 [Electronic] United States
• PMID: 26209628 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 by The American Association of Immunologists, Inc.

Chemical References

• Antibodies, Monoclonal
• Glucocorticoids
• Macrophage Migration-Inhibitory Factors
• Protein Isoforms
• Dexamethasone

Topics

• Animals
• Antibodies, Monoclonal (immunology, therapeutic use)
• Blotting, Western
• Dexamethasone (immunology, therapeutic use)
• Disease Models, Animal
• Enterocolitis (immunology, metabolism, prevention & control)
• Flow Cytometry
• Glomerulonephritis (immunology, metabolism, prevention & control)
• Glucocorticoids (immunology, therapeutic use)
• Humans
• Inflammation (immunology, metabolism, prevention & control)
• Macrophage Migration-Inhibitory Factors (chemistry, immunology, metabolism)
• Male
• Mice, Inbred C57BL
• Mice, Knockout
• Molecular Targeted Therapy (methods)
• Oxidation-Reduction
• Protein Conformation
• Protein Isoforms (chemistry, immunology, metabolism)
• Rabbits
• Rats, Inbred WKY