ABSTRACT
BACKGROUND: Studies of the role of the cytokine macrophage-migration-inhibitory-factor (MIF) in malignant tumors have revealed its stimulating influence on cell-cycle progression, angiogenesis and anti-apoptosis. RESULTS: Here we show that in vitro targeting MIF in cultures of human malignant glioblastoma cells by either antisense plasmid introduction or anti-MIF antibody treatment reduced the growth rates of tumor cells. Of note is the marked decrease of proliferation under confluent and over-confluent conditions, implying a role of MIF in overcoming contact inhibition. Several proteins involved in contact inhibition including p27, p21, p53 and CEBPalpha are upregulated in the MIF antisense clones indicating a restoration of contact inhibition in the tumor cells. Correspondingly, we observed a marked increase in MIF mRNA and protein content under higher cell densities in LN18 cells. Furthermore, we showed the relevance of the enzymatic active site of MIF for the proliferation of glioblastoma cells by using the MIF-tautomerase inhibitor ISO-1. CONCLUSION: Our study adds another puzzle stone to the role of MIF in tumor growth and progression by showing the importance of MIF for overcoming contact inhibition.
Subject(s)
Contact Inhibition/genetics , Glioblastoma/pathology , Intramolecular Oxidoreductases/genetics , Macrophage Migration-Inhibitory Factors/genetics , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Cell Proliferation/drug effects , Contact Inhibition/drug effects , Disease Progression , Gene Knockdown Techniques , Gene Targeting , Glioblastoma/genetics , Glioblastoma/metabolism , Humans , Intramolecular Oxidoreductases/antagonists & inhibitors , Intramolecular Oxidoreductases/immunology , Intramolecular Oxidoreductases/metabolism , Macrophage Migration-Inhibitory Factors/antagonists & inhibitors , Macrophage Migration-Inhibitory Factors/immunology , Macrophage Migration-Inhibitory Factors/metabolism , RNA, Small Interfering/pharmacology , TransfectionABSTRACT
MIF has been described as a protein that plays an essential role in both innate and acquired immunity. Previous studies have demonstrated that MIF activates lymphocytes, granulocytes and monocytes/macrophages. Furthermore, MIF can counteract the physiological function of steroids, thus playing a role in immune system regulation. Further evidence for a role of MIF in immunity was obtained in mouse models of autoimmune disorders, where the inhibition of MIF resulted in a more benign disease progression. This observation made MIF an attractive therapeutic target for the treatment of these disorders. Moreover, MIF expression was found to be upregulated in a variety of different tumor cells, a finding that further attracted interest. This review provides an overview of the involvement of MIF in both autoimmune disorders and tumorigenesis and summarizes the molecular action of MIF in this context.
