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MIF: a new cytokine link between rheumatoid arthritis and atherosclerosis

Key Points

  • Macrophage migration inhibitory factor (MIF) is a key cytokine in diseases characterized by disordered immune-inflammatory responses, such as rheumatoid arthritis (RA). In RA, MIF induces the expression of other disease-promoting cytokines, regulates hypercellularity and is required for leukocyte trafficking into the joint.

  • Atherosclerosis is now recognized as sharing many features with 'traditional' inflammatory diseases such as RA, including a dependence on the recruitment and activation of macrophages and disordered growth of resident cells. Recent studies have shown that MIF is expressed in human atheroma lesions and is functionally linked to atherogenesis and plaque formation in vivo.

  • Atherosclerosis is accelerated in patients with inflammatory diseases and there is growing evidence that it could be further exacerbated by glucocorticoid treatment. As MIF is unique among pro-inflammatory cytokines in that it can be induced by glucocorticoids, MIF could provide a link between inflammatory disease, glucocorticoid treatment and the development of atherosclerosis.

  • Traditional anticytokine therapy with recombinant proteins, such as monoclonal antibodies, would be expensive in diseases as prevalent as atheroma. MIF has unique structural features that favour the development of small-molecule MIF inhibitors, and examples of such compounds that are active in vivo in mouse models of inflammation, RA and atherosclerosis have been reported.

Abstract

Macrophage migration inhibitory factor (MIF) is well established as a key cytokine in immuno-inflammatory diseases such as rheumatoid arthritis. Inflammation is now also recognized as having a crucial role in atherosclerosis, and recent evidence indicates that MIF could also be important in this disease. Here, we review the role of MIF in rheumatoid arthritis and atherosclerosis, discuss the ways in which MIF and its relationship with glucocorticoids could link these diseases, and consider the potential of MIF as a new therapeutic target for small-molecule and antibody-based anti-cytokine drugs.

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Figure 1: Shared cellular mechanisms in the pathogenesis of rheumatoid arthritis and atherosclerosis.
Figure 2: Molecular mode of action of MIF.
Figure 3: MIF as a potential connection between inflammatory disease and atherosclerosis.
Figure 4: MIF as a potential connection between glucocorticoids, inflammatory pathways and atheroma.
Figure 5: Proposed actions of small-molecule MIF inhibitors.

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Acknowledgements

We are indebted to numerous collaborators with whom we were fortunate to collaborate on various aspects of MIF biochemistry, biology and disease correlations during recent years. E.F.M. and M.L. are supported by a Program Grant from the National Health and Medical Research Council, Australia, and a National Institutes of Health, USA, RO1 grant. J.B. was supported by grants from the Deutsche Forschungsgemeinschaft, Germany.

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Correspondence to Eric F. Morand.

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Competing interests

E.F.M. is a part-time employee and shareholder of Cortical Pty Ltd (Australia), a company involved in the development of small-molecule MIF antagonists, and is a co-inventor on patents relating to small-molecule MIF antagonists. M.L. is a consultant to Cortical Pty Ltd. J.B. is a co-inventor on a patent describing the use of MIF antibody for the treatment of inflammatory disease.

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DATABASES

OMIM

Rheumatoid arthritis

Glossary

Glucocorticoids

Commonly used anti-inflammatory drugs (often referred to as steroids in this context) originally derived from adrenal hormones.

Cytokine

A soluble product that enables cell–cell communication through its interaction with a specific receptor.

Matrix metalloproteinases

(MMPs). Degradative enzymes involved in connective tissue damage.

p53

A tumour-suppressor protein involved in the regulation of cell-cycle events, including apoptosis.

Synoviocyte

A cell that resides in the tissues that line the joints.

Foam cells

Fat-laden macrophages present in atherosclerotic lesions.

Neointimal lesion

A lesion formed as a result of the response of the vascular lining to damage that involves the production of new vessel lining.

Systemic lupus erythematosus

(SLE). An infrequent but serious systemic inflammatory and autoimmune disease that is associated with a high risk of atherosclerosis.

Cushing's syndrome

The clinical syndrome resulting from overexposure to glucocorticoids.

Isomerase/tautomerase

A class of enzymes that catalyse the conversion of one isomeric/tautomeric form of a molecule to another. MIF is an isomerase/tautomerase that catalyses a reaction in which D-2-carboxymethylester-2,3-dihydroindole-5,6-quinone is converted to 5,6-dihydroxyindole-2-carboxymethyl ester.

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Morand, E., Leech, M. & Bernhagen, J. MIF: a new cytokine link between rheumatoid arthritis and atherosclerosis. Nat Rev Drug Discov 5, 399–411 (2006). https://doi.org/10.1038/nrd2029

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