Macrophage migration inhibitory factor: Cytokine, hormone, or enzyme?

Swope, Melissa D.; Lolis, Elias

doi:10.1007/bfb0033647

Cited by 90 publications

(50 citation statements)

References 94 publications

(140 reference statements)

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“…Independent and simultaneous studies by Rorsman and colleagues, who were investigating the enzymatic pathway leading to melanin production, provided evidence that MIF catalyzed the tautomerization of the non-physiologic stereoisomer D-dopachrome, a precursor of melanin [9]. Although no physiologic enzymatic activity could be identified, this observation fueled interest into the possible catalytic function of MIF, which together with the lack of molecular information about a cell surface receptor, suggested that MIF mediated its immunologic action via an enzymatic reaction [10]. Site-directed mutagenesis of the protein's N-terminal, putative catalytic proline eliminated bioactivity in some studies [11,12], but not in others [13][14][15].…”

Section: Figurementioning

confidence: 99%

Insight into the biology of Macrophage Migration Inhibitory Factor (MIF) revealed by the cloning of its cell surface receptor

Leng

Bucala

2006

Cell Res

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Abbreviations: Alexa-MIF (Alexa-488-modified MIF); ERK-1/2 (extracellular signal-related kinase); KO (gene knock-out); LPS (lipopolysaccharide); MAPK (mitogen-activated protein kinase); MIF (macrophage migration inhibitory factor); RIP (regulated intramembrane proteolysis); sCD74 (soluble CD74 ectodomain); TLR-4 (Toll-like receptor 4). IntroductionThe protein mediator known as macrophage migration inhibitory factor (MIF) is considered to be one of the first cytokines to be discovered. In the late 1950s, "MIF" described an activity elaborated by activated lymphocytes that arrested the random movement of monocytes/macrophages [1]. This activity correlates with delayed-type hypersensitivity in vitro, and it induced significant interest among immunologists for representing a soluble, but non-immunoglobulin, factor that could be studied and manipulated in vitro. By 1966, John David and Barry Bloom independently described that MIF was most likely a protein that was secreted into the conditioned medium of activated lymphocytes [2,3], and immunologists soon measured MIF's eponymous activity by a capillary tube assay. However, MIF was difficult to isolate or clone, so as various other lymphokines (T cell growth factor/IL-2), monokines (endogenous pyrogen/IL-1; tumor necrosis factor/lymphotoxin), and interferons were systematically cloned and produced recombinantly and additional proteins, such as interferon-g and IL-4, were also observed to exhibit migration inhibitory activity, immunologic interest in MIF waned. It wasn't until 1989 that a discrete gene sequence was determined to be associated with MIF [4] and in 1993, pure recombinant protein became available for biologic and structure-function studies [5]. The threedimensional crystal structure of MIF was solved by three laboratories in 1996, thus revealing a new protein fold and structural superfamily with MIF as its defining member [6][7][8]. These studies also provided insights into the likely native form of the protein -a homotrimer with a MW of 37.5 kDa (Figure 1). Figure 1 Three-dimensional ribbon diagram of human MIF, revealing its homotrimeric subunit structure. From ref [7]. Each color denotes one monomer. Human MIF homotrimerCell Research (2006) The recent cloning of MIF receptor fills an important gap in our understanding of the molecular biology and immunology of MIF. The MIF receptor, like MIF, does not fall into any established family of protein mediators, providing both new challenges and opportunities for the structural and functional analysis of MIF signal transduction.

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Section: Figurementioning

confidence: 99%

Insight into the biology of Macrophage Migration Inhibitory Factor (MIF) revealed by the cloning of its cell surface receptor

Leng

Bucala

2006

Cell Res

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“…Once released, MIF activates the receptor CD74 in a complex with CD44 (13), or the chemokine receptors CXCR2 (14) and CXCR4 (15), initiating a cascade of intracellular signaling (16). One aspect of MIF that remains enigmatic is the presence of a catalytic site, highly conserved among all MIFs and present between subunits of the trimer (16)(17)(18)(19). No physiologic substrate for MIF has been identified, but "pseudosubstrates" have been found that allow for screening inhibitors at this site (20,21).…”

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confidence: 99%

Allosteric inhibition of macrophage migration inhibitory factor revealed by ibudilast

Cho¹,

Crichlow²,

Vermeire

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

174

159

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AV411 (ibudilast; 3-isobutyryl-2-isopropylpyrazolo-[1,5-a]pyridine) is an antiinflammatory drug that was initially developed for the treatment of bronchial asthma but which also has been used for cerebrovascular and ocular indications. It is a nonselective inhibitor of various phosphodiesterases (PDEs) and has varied antiinflammatory activity. More recently, AV411 has been studied as a possible therapeutic for the treatment of neuropathic pain and opioid withdrawal through its actions on glial cells. As described herein, the PDE inhibitor AV411 and its PDE-inhibition-compromised analog AV1013 inhibit the catalytic and chemotactic functions of the proinflammatory protein, macrophage migration inhibitory factor (MIF). Enzymatic analysis indicates that these compounds are noncompetitive inhibitors of the p-hydroxyphenylpyruvate (HPP) tautomerase activity of MIF and an allosteric binding site of AV411 and AV1013 is detected by NMR. The allosteric inhibition mechanism is further elucidated by X-ray crystallography based on the MIF/AV1013 binary and MIF/AV1013/HPP ternary complexes. In addition, our antibody experiments directed against MIF receptors indicate that CXCR2 is the major receptor for MIF-mediated chemotaxis of peripheral blood mononuclear cells.cross-reactivity | drug repositioning | cytokine | inflammation

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“…- ----------------------------------------------------------------------------------------------------It is generally believed that MIF functions as a cytokine to promote the recruitment of neutrophils and macrophages and the migration of these cells to the site of inflammation (20). MIF is involved in T-cell proliferation through promoting the secretion of interleukin-2 (21) and can deliver a priming signal to neutrophils to mobilize them to produce an immediate and robust response in the presence of pathogens (22).…”

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confidence: 99%

Functional promoter polymorphisms of macrophage migration inhibitory factor in peptic ulcer diseases

Shiroeda

Tahara²,

Shibata³

et al. 2010

Int J Mol Med

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Abstract. Macrophage migration inhibitory factor (MIF) is a key proinflammatory mediator, which plays a pivotal role in inflammatory and immune diseases. We attempted to clarify the association of functional polymorphisms of MIF gene promoter with the development of gastro-duodenal ulcer. The study was performed in 471 stocked DNAs obtained from the subjects, including 93 healthy volunteers, with no evidence of gastric malignancy. We employed the PCR-SSCP method to detect gene polymorphisms. In all 471 DNAs, 92 and 43 were obtained from gastric and duodenal ulcer patients, respectively. By an unadjusted analysis, infection with Helicobacter pylori (H. pylori), male gender and non-steroidal anti-inflammatory drug (NSAID/aspirin) use were significantly associated with a risk for developing a gastric ulcer, whereas MIF promoter polymorphisms were not. On the other hand, infection with H. pylori, male gender and 7-CATT repeat at position -794 were significantly associated with the development of a duodenal ulcer, whereas NSAID/ aspirin use was not. By the analysis after adjustment for age, gender, NSAID/aspirin use and H. pylori infection status, 7/7-CATT homozygote had a significantly increased risk for the development of duodenal ulcers (OR, 6.31; 95% CI, p=0.012). No factors were significantly associated with the development of peptic ulcers in NSAID/aspirin users. Our results suggested that tetranucleotide repeat polymorphism of MIF gene promoter might be associated with the development of duodenal ulcers.

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Macrophage migration inhibitory factor: Cytokine, hormone, or enzyme?

Cited by 90 publications

References 94 publications

Insight into the biology of Macrophage Migration Inhibitory Factor (MIF) revealed by the cloning of its cell surface receptor

Insight into the biology of Macrophage Migration Inhibitory Factor (MIF) revealed by the cloning of its cell surface receptor

Allosteric inhibition of macrophage migration inhibitory factor revealed by ibudilast

Functional promoter polymorphisms of macrophage migration inhibitory factor in peptic ulcer diseases

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