Autoimmunity and chronic low-grade inflammation are hallmarks of diabetes mellitus type one (T1DM) and type two (T2DM), respectively. Both processes are orchestrated by inflammatory cytokines, including the macrophage migration inhibitory factor (MIF). To date, MIF has been implicated in both types of diabetes; therefore, understanding the role of MIF could affect our understanding of the autoimmune or inflammatory responses that influence diabetic pathology. This review highlights our current knowledge about the involvement of MIF in both types of diabetes in the clinical environment and in experimental disease models. 1. Introduction MIF was originally reported in 1966 by two different groups and was described as a T cell derived cytokine that inhibited the random migration of macrophages in vitro and promoted macrophage accumulation during delayed-type hypersensitivity reactions [1, 2]. Human and mouse MIF genes are 90% homologous; MIF protein has a molecular weight of 12.5？kDa [3]. MIF is an evolutionarily conserved molecule that is constitutively expressed in many tissues and cells (Figure 1). Figure 1: MIF expression pattern. MIF, a cytokine, is distributed throughout almost the entire body. This is because MIF is part of the innate immune system or first line of immune defense. Moreover, MIF is stored in intracellular pools and therefore does not require immediate synthesis before secretion. MIF lacks an aminoterminal leader sequence; this indicates that MIF is released from cells through a nonconventional protein-secretion pathway [3]. After the discovery of MIF, several studies were conducted to establish its role in the immune response [4–6]. However, not until 1990 was MIF recognized as the first molecule to arrive at the inflammation site and the factor that likely determines the degree of cellular inflammation [7]. Different experimental strategies, including anti-MIF antibodies and knockout (KO) and transgenic MIF mice (MIF-Tg), have been used to establish that MIF counterregulates the immunosuppressive effects of steroids and to implicate MIF in tumor necrosis factor (TNFα) and nitric oxide (NO) production [8]; additionally, MIF was found to possess growth factor activity [9], overregulate the expression of Toll-like receptor (TLR)-4 on antigen-presenting cells [10], sustain macrophage proinflammatory abilities by inhibiting p53, and also possess tautomerase and oxidoreductase activities [11]. All the above-described inherent properties permitted the recognition of MIF as a critical molecule in proinflammatory innate immune responses and
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