Glucocorticoid counter regulation: macrophage migration inhibitory factor as a target for drug discovery.
Over the past year, human studies have confirmed and expanded the involvement of macrophage migration inhibitory factor (MIF) in a number of diseases that had originally been studied in animals. In addition to sepsis, rheumatoid arthritis, glomerulonephritis and inflammatory lung disease, elevated MIF levels have been described in patients suffering from ulcerative colitis, inflammatory neurological diseases and cancer. Cellular studies indicate that in addition to macrophages, MIF affects the activities of CD4+ and CD8+ T cells, natural killer cells, fibroblasts and endothelial cells, actions that may explain the contribution of MIF to inflammatory diseases and cancer. Molecular studies have identified direct interactions between MIF and several intracellular regulatory proteins (Jab1, PAG and p53) that control cellular growth and proliferation; however, how interactions with these proteins fit into a general scheme to explain MIF's biological activity has not been elucidated. The three-dimensional structure of MIF has offered some surprising clues and if the potential enzymatic sites identified are involved with MIF-associated diseases, they may provide good targets for therapeutic intervention.
Lolis
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Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06430, USA. elias.lolis@yale.edu
D048868:Adaptor Proteins, Signal Transducing; D000595:Amino Acid Sequence; D000818:Animals; D000075686:COP9 Signalosome Complex; D004268:DNA-Binding Proteins / Q000378:metabolism; D015195:Drug Design; D016158:Genes, p53; D005938:Glucocorticoids / Q000037:antagonists & inhibitors* / Q000502:physiology; D006801:Humans; D007249:Inflammation / Q000209:etiology / Q000276:immunology / Q000378:metabolism; D018836:Inflammation Mediators / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins; D008263:Macrophage Migration-Inhibitory Factors / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*; D008565:Membrane Proteins / Q000378:metabolism; D008969:Molecular Sequence Data; D009369:Neoplasms / Q000209:etiology / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000209:etiology / Q000378:metabolism; D010447:Peptide Hydrolases; D010750:Phosphoproteins / Q000378:metabolism; D013329:Structure-Activity Relationship; D014157:Transcription Factors / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D004268:DNA-Binding Proteins; D005938:Glucocorticoids; D018836:Inflammation Mediators; D047908:Intracellular Signaling Peptides and Proteins; D008263:Macrophage Migration-Inhibitory Factors; D008565:Membrane Proteins; C498710:PAG1 protein, human; D010750:Phosphoproteins; D014157:Transcription Factors; D010447:Peptide Hydrolases; C501488:COPS5 protein, human; C501490:Cops5 protein, mouse; D000075686:COP9 Signalosome Complex