Novel pathophysiological aspects of macrophage migration inhibitory factor (review).

Macrophage migration inhibitory factor (MIF) was the first T-cell-derived soluble lymphokine to be identified. It was originally found to inhibit the migration of macrophages and activate them at inflammatory loci. During the past few years, however, previously unrecognized properties of MIF have been discovered. It also functions, for example, as a pituitary hormone, glucocorticoid-induced immunomodulator and isomerase. We cloned rat MIF cDNA and reported that the nucleotide sequence of the cDNA predicts a protein consisting of 114 amino acids. Northern blot analysis indicated that the MIF mRNA was expressed in a wide variety of organs, including the brain, kidney, and liver. Following this, we demonstrated definitively that MIF was expressed in a variety of cells, suggesting its involvement in various biological events such as wound healing, atopic dermatitis, and, possibly, diabetes/obesity. Furthermore, we elucidated its physicochemical properties, including the tertiary structures of both human and rat MIF. These tertiary structures showed that this protein forms a homotrimer with each monomer consisting of two beta/alpha/beta motifs, thus resembling 5-carboxymethyl-2-hydroxymuconate isomerase and d-dopachrome tautomerase. From the available data on MIF, including ours, it is considered that the protein is associated not only with immune responses but also with cell growth and differentiation during wound repair and carcinogenesis. Thus, MIF could become a major target protein in a variety of pathophysiological states and anti-MIF antibodies and antagonists could be applied therapeutically in the clinical situation for treatment of various diseases. Bearing this in mind, this review discusses the role of MIF, considering its gene and protein structures as well as its pathophysiological functions in various organs and disease states, finally considering perspectives for the future.