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

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 healt...

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Veröffentlicht in:The Journal of immunology (1950) 2015-09, Vol.195 (5), p.2343-2352
Hauptverfasser: Thiele, Michael, Kerschbaumer, Randolf J, Tam, Frederick W K, Völkel, Dirk, Douillard, Patrice, Schinagl, Alexander, Kühnel, Harald, Smith, Jennifer, McDaid, John P, Bhangal, Gurjeet, Yu, Mei-Ching, Pusey, Charles D, Cook, H Terence, Kovarik, Josef, Magelky, Erica, Bhan, Atul, Rieger, Manfred, Mudde, Geert C, Ehrlich, Hartmut, Jilma, Bernd, Tilg, Herbert, Moschen, Alexander, Terhorst, Cox, Scheiflinger, Friedrich
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container_issue 5
container_start_page 2343
container_title The Journal of immunology (1950)
container_volume 195
creator Thiele, Michael
Kerschbaumer, Randolf J
Tam, Frederick W K
Völkel, Dirk
Douillard, Patrice
Schinagl, Alexander
Kühnel, Harald
Smith, Jennifer
McDaid, John P
Bhangal, Gurjeet
Yu, Mei-Ching
Pusey, Charles D
Cook, H Terence
Kovarik, Josef
Magelky, Erica
Bhan, Atul
Rieger, Manfred
Mudde, Geert C
Ehrlich, Hartmut
Jilma, Bernd
Tilg, Herbert
Moschen, Alexander
Terhorst, Cox
Scheiflinger, Friedrich
description 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.
doi_str_mv 10.4049/jimmunol.1500572
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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. 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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.</description><subject>Animals</subject><subject>Antibodies, Monoclonal - immunology</subject><subject>Antibodies, Monoclonal - therapeutic use</subject><subject>Blotting, Western</subject><subject>Dexamethasone - immunology</subject><subject>Dexamethasone - therapeutic use</subject><subject>Disease Models, Animal</subject><subject>Enterocolitis - immunology</subject><subject>Enterocolitis - metabolism</subject><subject>Enterocolitis - prevention &amp; control</subject><subject>Flow Cytometry</subject><subject>Glomerulonephritis - immunology</subject><subject>Glomerulonephritis - metabolism</subject><subject>Glomerulonephritis - prevention &amp; control</subject><subject>Glucocorticoids - immunology</subject><subject>Glucocorticoids - therapeutic use</subject><subject>Humans</subject><subject>Inflammation - immunology</subject><subject>Inflammation - metabolism</subject><subject>Inflammation - prevention &amp; 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Kerschbaumer, Randolf J ; Tam, Frederick W K ; Völkel, Dirk ; Douillard, Patrice ; Schinagl, Alexander ; Kühnel, Harald ; Smith, Jennifer ; McDaid, John P ; Bhangal, Gurjeet ; Yu, Mei-Ching ; Pusey, Charles D ; Cook, H Terence ; Kovarik, Josef ; Magelky, Erica ; Bhan, Atul ; Rieger, Manfred ; Mudde, Geert C ; Ehrlich, Hartmut ; Jilma, Bernd ; Tilg, Herbert ; Moschen, Alexander ; Terhorst, Cox ; Scheiflinger, Friedrich</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c429t-dee0da14c92041d6d78be2e20e3533dc2a914acd86c6b0106d54f442a295a3bb3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>Animals</topic><topic>Antibodies, Monoclonal - immunology</topic><topic>Antibodies, Monoclonal - therapeutic use</topic><topic>Blotting, Western</topic><topic>Dexamethasone - immunology</topic><topic>Dexamethasone - therapeutic use</topic><topic>Disease Models, Animal</topic><topic>Enterocolitis - immunology</topic><topic>Enterocolitis - metabolism</topic><topic>Enterocolitis - prevention &amp; 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subjects Animals
Antibodies, Monoclonal - immunology
Antibodies, Monoclonal - therapeutic use
Blotting, Western
Dexamethasone - immunology
Dexamethasone - therapeutic use
Disease Models, Animal
Enterocolitis - immunology
Enterocolitis - metabolism
Enterocolitis - prevention & control
Flow Cytometry
Glomerulonephritis - immunology
Glomerulonephritis - metabolism
Glomerulonephritis - prevention & control
Glucocorticoids - immunology
Glucocorticoids - therapeutic use
Humans
Inflammation - immunology
Inflammation - metabolism
Inflammation - prevention & control
Innate Immunity and Inflammation
Macrophage Migration-Inhibitory Factors - chemistry
Macrophage Migration-Inhibitory Factors - immunology
Macrophage Migration-Inhibitory Factors - metabolism
Male
Mice, Inbred C57BL
Mice, Knockout
Molecular Targeted Therapy - methods
Oxidation-Reduction
Protein Conformation
Protein Isoforms - chemistry
Protein Isoforms - immunology
Protein Isoforms - metabolism
Rabbits
Rats, Inbred WKY
title Selective Targeting of a Disease-Related Conformational Isoform of Macrophage Migration Inhibitory Factor Ameliorates Inflammatory Conditions
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