MIF (or macrophage migration inhibitory factor) was the first lymphokine/cytokine to be recognized in the pregenomics era [1, 2]. Regardless, it is one of the least understood of all inflammatory mediators [1, 3]. Mouse MIF is a 12.5 kDa, 115 amino acid (aa) nonglycosylated polypeptide that is synthesized without a signal sequence [4-7]. Secretion occurs nonclassically via an ABCA1 transporter [6]. The initiating Met is removed, leaving Pro as the first amino acid. The molecule consists of two alpha -helices and six beta -strands, four of which form a beta -sheet. The two remaining beta -strands interact with other MIF molecules, creating a trimer [2, 8]. Structure-function studies suggests MIF is bifunctional with segregated topology. The N- and C-termini mediate enzyme activity (in theory). Phenylpyruvate tautomerase activity (enol- to-keto) has been demonstrated and is dependent upon Pro at position #1 [9]. Amino acids 3-23 have also been shown to be reminescent of a GST glutathione-binding domain [10]. MIF has proinflammatory cytokine activity centered on aa’s 49-65. On fibroblasts, MIF induces, IL-1, IL-8 and MMP expression; on macrophages, MIF stimulates, NO production and TNF-alpha release following IFN-gamma activation [11, 12]. Mouse MIF apparently acts through CD74 and CD44, likely in some form of trimeric interaction [13, 14]. Mouse MIF is active on human cells, while human MIF is active on mouse cells [12]. Mouse MIF is 99%, 84%, 90%, and 90% aa identical to rat, porcine, bovine and human MIF, respectively.
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