Macrophage migration inhibitory factor and CD74 antigen (MIF/CD74)

Macrophage migration inhibitory factor (MIF) is a pleiotropic pro-inflammatory cytokine that acts as a key mediator of the innate and adaptive immune responses (UniProt P14174). Its primary high-affinity receptor is CD74, the HLA class II-associated invariant chain, which is expressed on the surface of various immune and malignant cells (UniProt P04233). The binding of MIF to CD74 initiates a signaling cascade, typically requiring the recruitment of the co-receptor CD44, which activates the ERK1/2, AKT, and NF-κB pathways to promote cell survival and proliferation (Leng et al., 2003, PMID: 12692550). This MIF-CD74 axis is frequently overexpressed in cancers such as multiple myeloma and melanoma, where it facilitates immune evasion and tumor progression, as well as in autoimmune conditions like rheumatoid arthritis and systemic lupus erythematosus (Borghese & Clanchy, 2011, PMID: 21455401). Therapeutic interventions targeting this complex include the anti-CD74 monoclonal antibody milatuzumab and the anti-MIF antibody imalumab, which aim to disrupt pathological signaling (Berkova et al., 2010, PMID: 20143110). Additionally, small-molecule inhibitors like ISO-1 target the tautomerase active site of MIF to prevent its interaction with CD74 (Lubetsky et al., 2002, PMID: 11932191).

Other names

MIFCD74HLA class II-associated invariant chainIiGlycosylation-inhibiting factor (GIF)L-dopachrome isomerasePhenylpyruvate tautomerasep33p35p41

The mechanism of action involves the disruption of the MIF-CD74 signaling axis. This is achieved either through monoclonal antibodies that neutralize the MIF cytokine or bind to the CD74 receptor to block ligand interaction, or through small-molecule inhibitors that target the MIF tautomerase active site, thereby preventing the activation of pro-survival and pro-inflammatory pathways such as ERK1/2, AKT, and NF-κB (PMID: 12692550, PMID: 20143110, PMID: 11932191).