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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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. 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><identifier>ISSN: 0022-1767</identifier><identifier>EISSN: 1550-6606</identifier><identifier>DOI: 10.4049/jimmunol.1500572</identifier><identifier>PMID: 26209628</identifier><language>eng</language><publisher>United States: AAI</publisher><subject>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</subject><ispartof>The Journal of immunology (1950), 2015-09, Vol.195 (5), p.2343-2352</ispartof><rights>Copyright © 2015 by The American Association of Immunologists, Inc.</rights><rights>Copyright © 2015 by The American Association of Immunologists, Inc. 2015 Copyright © 2015 by The American Association of Immunologists, Inc.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c429t-dee0da14c92041d6d78be2e20e3533dc2a914acd86c6b0106d54f442a295a3bb3</citedby><cites>FETCH-LOGICAL-c429t-dee0da14c92041d6d78be2e20e3533dc2a914acd86c6b0106d54f442a295a3bb3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,776,780,881,27901,27902</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/26209628$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Thiele, Michael</creatorcontrib><creatorcontrib>Kerschbaumer, Randolf J</creatorcontrib><creatorcontrib>Tam, Frederick W K</creatorcontrib><creatorcontrib>Völkel, Dirk</creatorcontrib><creatorcontrib>Douillard, Patrice</creatorcontrib><creatorcontrib>Schinagl, Alexander</creatorcontrib><creatorcontrib>Kühnel, Harald</creatorcontrib><creatorcontrib>Smith, Jennifer</creatorcontrib><creatorcontrib>McDaid, John P</creatorcontrib><creatorcontrib>Bhangal, Gurjeet</creatorcontrib><creatorcontrib>Yu, Mei-Ching</creatorcontrib><creatorcontrib>Pusey, Charles D</creatorcontrib><creatorcontrib>Cook, H Terence</creatorcontrib><creatorcontrib>Kovarik, Josef</creatorcontrib><creatorcontrib>Magelky, Erica</creatorcontrib><creatorcontrib>Bhan, Atul</creatorcontrib><creatorcontrib>Rieger, Manfred</creatorcontrib><creatorcontrib>Mudde, Geert C</creatorcontrib><creatorcontrib>Ehrlich, Hartmut</creatorcontrib><creatorcontrib>Jilma, Bernd</creatorcontrib><creatorcontrib>Tilg, Herbert</creatorcontrib><creatorcontrib>Moschen, Alexander</creatorcontrib><creatorcontrib>Terhorst, Cox</creatorcontrib><creatorcontrib>Scheiflinger, Friedrich</creatorcontrib><title>Selective Targeting of a Disease-Related Conformational Isoform of Macrophage Migration Inhibitory Factor Ameliorates Inflammatory Conditions</title><title>The Journal of immunology (1950)</title><addtitle>J Immunol</addtitle><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.</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 & control</subject><subject>Flow Cytometry</subject><subject>Glomerulonephritis - immunology</subject><subject>Glomerulonephritis - metabolism</subject><subject>Glomerulonephritis - prevention & 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 & control</subject><subject>Innate Immunity and Inflammation</subject><subject>Macrophage Migration-Inhibitory Factors - chemistry</subject><subject>Macrophage Migration-Inhibitory Factors - immunology</subject><subject>Macrophage Migration-Inhibitory Factors - metabolism</subject><subject>Male</subject><subject>Mice, Inbred C57BL</subject><subject>Mice, Knockout</subject><subject>Molecular Targeted Therapy - methods</subject><subject>Oxidation-Reduction</subject><subject>Protein Conformation</subject><subject>Protein Isoforms - chemistry</subject><subject>Protein Isoforms - immunology</subject><subject>Protein Isoforms - metabolism</subject><subject>Rabbits</subject><subject>Rats, Inbred WKY</subject><issn>0022-1767</issn><issn>1550-6606</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqNkUFv1DAQhS0Eokvhzgn5yCVl7DjO5oJUbSms1AoJytma2JOsKyde7Gyl_gj-MwndVnDjNBq97z2N_Rh7K-BMgWo-3PphOIwxnIkKoKrlM7YSVQWF1qCfsxWAlIWodX3CXuV8CwAapHrJTqSW0Gi5XrFf3ymQnfwd8RtMPU1-7HnsOPILnwkzFd8o4ESOb-LYxTTg5OOIgW9zXNaFvUab4n6HPfFr36c_BN-OO9_6KaZ7fol2nvx8oODjLFOe1S7gMIct-pzs_GLKr9mLDkOmN8d5yn5cfrrZfCmuvn7ebs6vCqtkMxWOCBwKZRsJSjjt6nVLkiRQWZWlsxIbodC6tba6BQHaVapTSqJsKizbtjxlHx9y94d2IGdpnBIGs09-wHRvInrzrzL6nenjnVGVKhuo54D3x4AUfx4oT2bw2VIIOFI8ZCNqIStd1434DxS0FCC0nFF4QOf_zDlR93SRALMUbh4LN8fCZ8u7v1_yZHhsuPwNyZmtHw</recordid><startdate>20150901</startdate><enddate>20150901</enddate><creator>Thiele, Michael</creator><creator>Kerschbaumer, Randolf J</creator><creator>Tam, Frederick W K</creator><creator>Völkel, Dirk</creator><creator>Douillard, Patrice</creator><creator>Schinagl, Alexander</creator><creator>Kühnel, Harald</creator><creator>Smith, Jennifer</creator><creator>McDaid, John P</creator><creator>Bhangal, Gurjeet</creator><creator>Yu, Mei-Ching</creator><creator>Pusey, Charles D</creator><creator>Cook, H Terence</creator><creator>Kovarik, Josef</creator><creator>Magelky, Erica</creator><creator>Bhan, Atul</creator><creator>Rieger, Manfred</creator><creator>Mudde, Geert C</creator><creator>Ehrlich, Hartmut</creator><creator>Jilma, Bernd</creator><creator>Tilg, Herbert</creator><creator>Moschen, Alexander</creator><creator>Terhorst, Cox</creator><creator>Scheiflinger, Friedrich</creator><general>AAI</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>7T5</scope><scope>H94</scope><scope>5PM</scope></search><sort><creationdate>20150901</creationdate><title>Selective Targeting of a Disease-Related Conformational Isoform of Macrophage Migration Inhibitory Factor Ameliorates Inflammatory Conditions</title><author>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</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 - 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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.</abstract><cop>United States</cop><pub>AAI</pub><pmid>26209628</pmid><doi>10.4049/jimmunol.1500572</doi><tpages>10</tpages><oa>free_for_read</oa></addata></record> |
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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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