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  • Review Article
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Macrophage migration inhibitory factor: a regulator of innate immunity

Nature Reviews Immunology volume 3, pages 791–800 (2003)Cite this article

Key Points

  • Cytokines are essential effector molecules of innate immunity that initiate and coordinate the cellular and humoral responses aimed, for example, at the eradication of microbial pathogens.

  • Discovered in the late 1960s as a product of activated T cells, the cytokine macrophage migration inhibitory factor (MIF) has been discovered recently to carry out important functions as a mediator of the innate immune system.

  • Constitutively expressed by a broad spectrum of cells and tissues, including monocytes and macrophages, MIF is rapidly released after exposure to microbial products and pro-inflammatory mediators, and in response to stress. After it is released, MIF induces pro-inflammatory biological responses that act as a regulator of immune responses.

  • MIF activates the extracellular signal-regulated kinase 1 (ERK1)/ERK2–mitogen-activated protein kinase pathway, inhibits the activity of JUN activation domain-binding protein 1 (JAB1) — a co-activator of the activator protein 1 (AP1) — upregulates the expression of Toll-like receptor 4 to promote the recognition of endotoxin-expressing bacterial pathogens, sustains pro-inflammatory function by inhibiting p53-dependent apoptosis of macrophages and counter-regulates the immunosuppressive effects of glucocorticoids on immune cells.

  • As a pro-inflammatory mediator, MIF has been shown to be implicated in the pathogenesis of severe sepsis and septic shock, acute respiratory distress syndrome, and several other inflammatory and autoimmune diseases, including rheumatoid arthritis, glomerulonephritis and inflammatory bowel diseases.

  • Given its crucial role as a regulator of innate and acquired immunity, pharmacological or immunological modulation of MIF activity might offer new treatment opportunities for the management of acute and chronic inflammatory diseases.

Abstract

For more than a quarter of a century, macrophage migration inhibitory factor (MIF) has been a mysterious cytokine. In recent years, MIF has assumed an important role as a pivotal regulator of innate immunity. MIF is an integral component of the host antimicrobial alarm system and stress response that promotes the pro-inflammatory functions of immune cells. A rapidly increasing amount of literature indicates that MIF is implicated in the pathogenesis of sepsis, and inflammatory and autoimmune diseases, suggesting that MIF-directed therapies might offer new treatment opportunities for human diseases in the future.

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Figure 1: Structure of the human MIF gene.
Figure 2: Three-dimensional structural homology of MIF and bacterial isomerase.
Figure 3: Pattern of MIF expression.
Figure 4: Mode of action of MIF.

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Acknowledgements

We thank M. Pagni for preparing figure 2 and J. Bernhagen for critical reading of the manuscript. The work was supported by the Swiss National Science Foundation, the Leenaards Foundation, the Santos Suarez Foundation and the Bristol-Myers Squibb Foundation. T. C. and T. R. are recipients of career and research awards of the Leenaards Foundation.

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Authors and Affiliations

  1. Division of Infectious Diseases, Department of Internal Medicine, Centre Hospitalier Universitaire Vaudois, Lausanne, CH-1011, Switzerland

    Thierry Calandra & Thierry Roger

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  1. Thierry Calandra
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Correspondence to Thierry Calandra.

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DATABASES

LocusLink

CD74

COX2

DDT

IFN-γ

IL-1

IL-12

JAB1

KIP1

MIF

p53

PLA2

TLR4

TNF

Glossary

TOLL-LIKE RECEPTORS

(TLRs). A family of receptors that recognize conserved products unique to microorganisms (such as lipopolysaccharide). Stimulation through TLRs induces dendritic-cell maturation and activation, leading to optimal activation of the adaptive immune response. TLR-mediated events signal to the host that a microbial pathogen is present.

DELAYED-TYPE HYPERSENSITIVITY

(DTH). A T-cell-mediated immune response marked by monocyte/macrophage infiltration and activation. DTH skin tests have classically been used for the diagnosis of infection with intracellular pathogens, such as Mycobacterium tuberculosis, and as a measure of the vigour of the cellular immune system. Classical DTH responses to intracellular pathogens depend on CD4+ T cells producing a T helper 1-type profile of cytokines (interferon-γ and tumour-necrosis factor).

SYNTENIC CONSERVATION

Conserved synteny refers to the situation in which two linked loci in one species have homologues that are also linked in another species, indicating similarities in content and organization between chromosomes of different species. Genes encoding macrophage migration inhibitory factor, matrix metalloproteinase 11 and glutathione S-transferase θ2 are all positioned on human chromosome 22q11.2 and at 40.9 centimorgans on mouse chromosome 10.

CD74

CD74, also known as the MHC class-II-associated invariant chain (Ii), is implicated in the transport of MHC class II proteins from the endoplasmic reticulum to the Golgi complex. About 5% of the cellular content of CD74 is expressed at the cell surface independently of MHC class II molecules. The intracellular domain of CD74 does not seem to contain sequences that are known to interact with signalling molecules.

T HELPER 1/2 CELLS

(TH1/TH2). Subsets of CD4+ T cells that are characterized by distinctive profiles of cytokine expression. TH1 cells typically produce interleukin-2 (IL-2), IL-12 and interferon-γ that support macrophage activation and the development of a cellular-based immune response, whereas TH2 cells typically produce IL-4, IL-5 and IL-13 that drive a humoral-based immune response.

YEAST TWO-HYBRID SYSTEM

A screening system for protein–protein interactions, which results in the transcription of a reporter gene when a 'bait' protein that is attached to a DNA-binding domain comes into contact with a 'prey' protein bound to a transcriptional activator.

ENDOCYTOSIS

A process whereby extracellular material is internalized by a cell, which can occur either in a receptor-independent and often non-specific manner (for example, by pinocytosis) or in a receptor-dependent manner. Both clathrin-dependent endocytosis and clathrin-independent internalization triggered by lipid rafts can occur.

CAECAL LIGATION AND PUNCTURE

(CLP). An experimental model of infection that mimics human peritonitis. After laparotomy, the caecum is ligated distal to the ileocecal valve and punctured with a calibrated needle to produce leakage of faeces into the peritoneal cavity. The caecum is then returned to the peritoneal cavity and the abdomen is closed. CLP induces physiological changes that are similar to those seen in humans with spontaneous or post-surgical peritonitis.

MICROBIAL SUPERANTIGENS

Molecules expressed by certain bacteria, viruses and mycoplasma that bind to the Vβ-chain of the T-cell receptor and the MHC class II molecule of antigen-presenting cells, causing the activation of large subsets of T cells that express Vβ-chains specific for the given superantigen.

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Calandra, T., Roger, T. Macrophage migration inhibitory factor: a regulator of innate immunity. Nat Rev Immunol 3, 791–800 (2003). https://doi.org/10.1038/nri1200

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