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

Thiele, Michael; Kerschbaumer, Randolf J.; Tam, Frederick W.K.; Völkel, Dirk; Douillard, Patrice; Schinagl, Alexander; Kühnel, Harald; Smith, Jennifer; McDaid, John; Bhangal, Gurjeet; Yu, Mei‐Ching; Pusey, Charles D.; Cook, H. Terence; Kovařík, Josef; Magelky, Erica; Bhan, Atul K.; Rieger, Manfred; Mudde, Geert C.; Ehrlich, Hartmut J.; Jilma, Bernd; Tilg, Herbert; Moschen, Alexander R.; Terhorst, Cox; Scheiflinger, Friedrich

doi:10.4049/jimmunol.1500572

Cited by 45 publications

(108 citation statements)

References 50 publications

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“…This hypothesis is supported by our finding that suprahepatic, but not peripheral, MIF correlated with bilirubin, AST, GGT and circulating triglycerides, as well as with short-term mortality in AH patients. It will also be important in future experiments to determine if there are post-translational modifications to MIF in patients with AH, such as the redox-dependent conformational isoforms reported in other inflammatory diseases[35]. …”

Section: Discussionmentioning

confidence: 99%

Hepatocyte-derived macrophage migration inhibitory factor mediates alcohol-induced liver injury in mice and patients

Marin

Poulsen²,

Òdena

et al. 2017

Journal of Hepatology

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Background & aims Macrophage migration inhibitory factor (MIF) is a multi-potent cytokine that contributes to the inflammatory response to injury. MIF is expressed by multiple cell types; however, the cellular source and actions of MIF in alcoholic liver disease (ALD) are not well known. Here we tested the hypothesis that non-myeloid cells, specifically hepatocytes, are an important cellular source of MIF in ALD. Methods MIF expression was measured in HuH7 and differentiated THP-1 cells in response to ethanol. Ethanol-induced liver injury was assessed in C57BL/6 (WT) and Mif−/− bone marrow chimeras. MIF was measured in peripheral and suprahepatic serum, as well as visualized by immunohistochemistry in liver biopsies, from patients with alcoholic hepatitis (AH). Results HuH7 hepatocytes, but not THP-1 macrophages, released MIF in response to challenge with ethanol in culture. In chimeric mice expressing MIF in non-myeloid cells (Mif−/− →WT), chronic ethanol feeding increased ALT/AST, hepatic steatosis, and expression of cytokine/chemokine mRNA. In contrast, chimeric mice not expressing MIF in non-myeloid cells (WT→ Mif−/−) were protected from ethanol-induced liver injury. Immunohistochemical staining of liver biopsies from patients with AH revealed a predominant localization of MIF to hepatocytes. Interestingly, the concentration of MIF in suprahepatic serum, but not peripheral serum, was positively correlated with clinical indicators of disease severity and with an increased risk of mortality in patients with AH. Conclusions Taken together, these data provide evidence that hepatocyte-derived MIF is critical to the pathogenesis of ALD in mice and likely contributes to liver injury in patients with AH.

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Section: Discussionmentioning

confidence: 99%

Hepatocyte-derived macrophage migration inhibitory factor mediates alcohol-induced liver injury in mice and patients

Marin

Poulsen²,

Òdena

et al. 2017

Journal of Hepatology

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“…More recently, the ability of this cytokine to support tumor progression has been highlighted, revealing MIF as a potential target for anticancer therapies in melanoma and colon cancer (40). MIF occurs in immunologically distinct conformational isoforms, reduced MIF and oxidized MIF (oxMIF), with the latter predominantly expressed in patients with inflammatory diseases (41) and is highly expressed by various cancer cell lines (42). This has led to the evaluation of an oxMIF ¼ blocking antibody (imalumab) in early-phase clinical studies of selected solid tumors (https://clinicaltrials.gov/ct2/show/ NCT01765790).…”

Section: Discussionmentioning

confidence: 99%

MIF-Induced Stromal PKCβ/IL8 Is Essential in Human Acute Myeloid Leukemia

et al. 2017

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Acute myeloid leukemia (AML) cells exhibit a high level of spontaneous apoptosis when cultured in vitro but have a prolonged survival time in vivo, indicating that tissue microenvironment plays a critical role in promoting AML cell survival. In vitro studies have shown that bone marrow mesenchymal stromal cells (BM-MSC) protect AML blasts from spontaneous and chemotherapy-induced apoptosis. Here, we report a novel interaction between AML blasts and BM-MSCs, which benefits AML proliferation and survival. We initially examined the cytokine profile in cultured human AML compared with AML cultured with BM-MSCs and found that macrophage migration inhibitory factor (MIF) was highly expressed by primary AML, and that IL8 was increased in AML/BM-MSC cocultures. Recombinant MIF increased IL8 expression in BMMSCs via its receptor CD74. Moreover, the MIF inhibitor ISO-1 inhibited AML-induced IL8 expression by BM-MSCs as well as BM-MSC-induced AML survival. Protein kinase C b (PKCb) regulated MIF-induced IL8 in BM-MSCs. Finally, targeted IL8 shRNA inhibited BM-MSC-induced AML survival. These results describe a novel, bidirectional, prosurvival mechanism between AML blasts and BM-MSCs. Furthermore, they provide biologic rationale for therapeutic strategies in AML targeting the microenvironment, specifically MIF and IL8.

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“…In inflammatory diseases, oxMIF was detected in the circulation of patients, therefore representing a systemic marker of inflammation [40]. In contrast, in cancer indications plasma levels of oxMIF were significantly elevated in samples from ovarian cancer patients, but not in patients with other solid tumor types investigated.…”

Section: Discussionmentioning

confidence: 99%

Oxidized macrophage migration inhibitory factor is a potential new tissue marker and drug target in cancer

Schinagl¹,

Thiele²,

Douillard³

et al. 2016

Oncotarget

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Macrophage migration inhibitory factor (MIF) is a pleiotropic cytokine, which was shown to be upregulated in cancers and to exhibit tumor promoting properties. Unlike other cytokines, MIF is ubiquitously present in the circulation and tissue of healthy subjects. We recently described a previously unrecognized, disease-related isoform of MIF, designated oxMIF, which is present in the circulation of patients with different inflammatory diseases. In this article, we report that oxMIF is also linked to different solid tumors as it is specifically expressed in tumor tissue from patients with colorectal, pancreatic, ovarian and lung cancer. Furthermore, oxMIF can be specifically targeted by a subset of phage display-derived fully human, monoclonal anti-MIF antibodies (mAbs) that were shown to neutralize pro-tumorigenic activities of MIF in vivo. We further demonstrate that anti-oxMIF mAbs sensitize human cancer cell lines (LNCaP, PC3, A2780 and A2780ADR) to the action of cytotoxic drugs (mitoxantrone, cisplatin and doxorubicin) in vitro and in an A2780 xenograft mouse model of ovarian cancer. We conclude that oxMIF is the disease related isoform of MIF in solid tumors and a potential new diagnostic marker and drug target in cancer.

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

Cited by 45 publications

References 50 publications

Hepatocyte-derived macrophage migration inhibitory factor mediates alcohol-induced liver injury in mice and patients

Hepatocyte-derived macrophage migration inhibitory factor mediates alcohol-induced liver injury in mice and patients

MIF-Induced Stromal PKCβ/IL8 Is Essential in Human Acute Myeloid Leukemia

Oxidized macrophage migration inhibitory factor is a potential new tissue marker and drug target in cancer

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