MIF, a controversial cytokine: a review of structural features, challenges, and opportunities for drug development

Abstract

Macrophage migration inhibitory factor (MIF) has emerged as a promising drug target in diseases including sepsis, rheumatoid arthritis, and cancer. MIF has multiple properties that favor development of specific, targeted therapies: it is expressed broadly among human cells, has noted roles in diverse inflammatory and oncological processes, and has intrinsic enzymatic activity amenable to high-throughput screening. Despite these advantages, anti-MIF therapy remains well behind other cytokine-targeted therapeutics, with no small molecules in the pipeline for clinical development and anti-MIF antibodies only recently beginning clinical trials. Areas covered: In this review we summarize current literature regarding MIF structure and function-including challenges and controversies that have arisen in studies of anti-MIF therapeutics-and propose a strategy for development of clinically relevant anti-MIF drugs. Expert opinion: We believe that the field of anti-MIF therapeutics would benefit from capitalizing on the protein's multiple assets while acknowledging their flaws. The tautomerase enzymatic site of MIF may not be active biologically, but can nonetheless offer a high-throughput method to highlight molecules of interest that can affect its other, frequently intertwined bioactivities. Future work should also focus on developing more robust assays for MIF bioactivity that can be used for second-pass screening and specificity studies.

Role of macrophage migration inhibitory factor in head and neck cancer and novel therapeutic targets: A systematic review

“…With regard to potential modifications at the protein level, MIF has long been assumed to not be subjected to posttranslational changes. There is, however, 1 exception: cysteinylation of Cys‐59 in human suppressor T cells was found to produce the glycosylation‐inhibiting factor variant of the protein . Moreover, recent evidence shows that MIF can be also modified by O‐GlcNAcylation at Ser‐112/Thr‐113, which leads to novel functions of MIF, such as inhibition of the EGFR .…”

“…In the future, the most important difficulties to overcome for the utilization of MIF pathway blockade are concerns regarding the heterogeneity of MIF binding partners and the lack of knowledge about the biological role of MIF. First, MIF may interact with at least 4 surface receptors and with multiple intracellular proteins, possibly reducing the efficiency of the targeted effect . Second, MIF is known to have a biological role in many physiological pathways, including immunological, metabolic, hormonal, chemotactic, posttranslational, and neurologic activities .…”

“…There is, however, 1 exception: cysteinylation of Cys-59 in human suppressor T cells was found to produce the glycosylation-inhibiting factor variant of the protein. 18 Moreover, recent evidence shows that MIF can be also modified by O-GlcNAcylation at Ser-112/Thr-113, which leads to novel functions of MIF, such as inhibition of the EGFR. 19 Indeed, Zheng et al 19 found that the modified MIF protein binds to EGFR, thereby inhibiting the F IGUR E 1 Migration inhibitory factor (MIF) structure.…”

“…First, MIF may interact with at least 4 surface receptors and with multiple intracellular proteins, possibly reducing the efficiency of the targeted effect. 18 Second, MIF is known to have a biological role in many physiological pathways, including immunological, metabolic, hormonal, chemotactic, posttranslational, and neurologic activities. 12 Thus far, it is difficult to predict the potential effect of anti-MIF/CD74/ CD44 therapies on patient homeostasis.…”

Analysis of serum macrophage migration inhibitory factor and D‐dopachrome tautomerase in systemic sclerosis

“…MIF has been shown to play a role in disease progression of autoimmune and inflammatory disorders, including rheumatoid arthritis, systemic lupus erythematosus (SLE), inflammatory bowel disease and multiple sclerosis 3, 4, 5. Studies have suggested possible associations between MIF and SSc, but the relationship between the two is unclear.…”