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Discovery of Human Macrophage Migration Inhibitory Factor (MIF)-CD74 Antagonists via Virtual Screening

January 12, 2010

Macrophage migration inhibitory factor (MIFa) is an immunoregulatory
and proinflammatory cytokine that is released by
many cell types including macrophages and T-cells. Cytokines
have been shown to be involved in the pathology of many
human inflammatory diseases. As a cytokine that is detectable
in circulation as well as in inflamed sites, MIF is implicated in
several inflammatory and autoimmune diseases including rheumatoid
arthritis, atherosclerosis, asthma, and lupus.1-3 MIF also
is involved in multiple aspects of tumor growth including control
of cell proliferation and promotion of angiogenesis.4,5 The
central role of MIF in tumorigenesis has been further supported
by genetic data showing that individuals with high expression
alleles of the MIF gene are at greater risk for the development
of invasive prostate cancer.6
The mechanism by which MIF acts as a proinflammatory
mediator and thereby controls local and systemic immune
responses is still unknown. An increasing body of evidence
suggests that (a) MIF is indirectly promoting angiogenesis by
stimulating tumor cells to produce angiogenic factors, such as
IL-8 and VEGF,5 (b) MIF directly down-regulates the expression
and function of the tumor-suppressor protein p53,7 (c) MIF is
activating MAPKs,8,9 thereby enhancing cellular responses,10
and(d)MIFcounter-regulates theexpressionof glucocorticoids,11,12
which suppress the expression and release of many proinflammatory
molecules. Recent studies have shown that MIF signal
transduction is initiated by binding to a transmembrane protein,
CD74.13,14 Inhibition of MIF-CD74 binding has been shown to
attenuate tumor growth and angiogenesis.4


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