Macrophage migration inhibitory factor (MIF) is a cytokine which also exhibits enzymatic properties like oxidoreductase and tautomerase. MIF plays a pivotal role in innate and acquired immunity as well as in the neuroendocrine axis. Since it is involved in the pathogenesis of acute and chronic inflammation, neoangiogenesis, and cancer, MIF and its signaling components are considered suitable targets for therapeutic intervention in several fields of medicine. In neurodegenerative and neurooncological diseases, MIF is a highly relevant, but still a hardly investigated mediator. MIF operates via intracellular protein-protein interaction as well as in CD74/CXCR2/CXCR4 receptor-mediated pathways to regulate essential cellular systems such as redox balance, HIF-1, and p53-mediated senescence and apoptosis as well as multiple signaling pathways. Acting as an endogenous glucocorticoid antagonist, MIF thus represents a relevant resistance gene in brain tumor therapies. Alongside this dual action, a functional homolog-annotated D-dopachrome tautomerase/MIF-2 has been uncovered utilizing the same cell surface receptor signaling cascade as MIF. Here we review MIF actions with respect to redox regulation in apoptosis and in tumor growth as well as its extracellular function with a focus on its potential role in brain diseases. We consider the possibility of MIF targeting in neurodegenerative processes and brain tumors by novel MIF-neutralizing approaches. 1. Introduction Macrophage migration inhibitory factor was one of the first cytokines identified after interferon [1] and represents a key regulator of the immune system (MIF is historically also known as glycosylation-inhibiting factor, GIF) [2, 3]. MIF was initially described as a proinflammatory soluble factor derived from T cells under various conditions such as delayed-type hypersensitivity responses and inflammation guiding site-specific migration of immunocompetent cells [2, 4]. It soon became apparent that MIF possesses immunoregulatory effects and is even constitutively detectable in various body fluids and cells of the mammalian organism. MIF levels are higher at sites of inflammation, within immune and brain cells and various cancer cells (Figure 1). Later, MIF was shown to contribute to neuroendocrine modulation, as a pituitary gland-derived hormone, inflammation, atherosclerosis, cancer development, and cancer progression [5–11]. MIF was first cloned from T cells in 1989, which revealed not only its primary sequence and conserved domains but also led to the discovery that MIF exhibits two catalytic
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