Interferon-y regulation of TNFα-induced matrix metalloproteinase 3 expression and migration of human glioma T98G cells

Induction of proinflammatory cytokines in response to malignant cells is an integral component of immune response to control tumor development. However, recent evidences have suggested that tumor cells may evade the immune system and exploit inflammatory responses to enhance its own growth. An exemplary example is the highly invasive and tumor necrosis factor (TNF)alpha-resistant glioblastoma, whose growth is associated with TNF alpha expression. We thus examined whether the tumor takes advantage of TNF alpha overexpression to enhance its invasiveness. To delineate the contribution of inflammation in tumor migration, we demonstrated that the role of proinflammatory cytokines on matrix metalloproteinases-3 (MMP-3) expression, and its consequent effects on the invasiveness of a human glioma cell-line, T98G. By using Matrigel Invasion Chamber, T98G cell migration was significantly enhanced in response to TNFa. In contrast, interferon-gamma (IFN gamma) reduced both basal and TNF alpha-enhanced cell invasion. To investigate the mechanisms involved, we demonstrated that TNF alpha upregulated mRNA and protein expression of MMP-3 in T98G cells, whereas IFN gamma downregulated the MMP-3 expression. The role of MMP-3 in glioma invasiveness was further confirmed by transfecting MMP-3 siRNA in T98G to abrogate the TNF alpha-enhanced cell invasion. To delineate the mechanisms further, we showed that IFN gamma exerts an inhibitory effect on the binding of TNF gamma-activated Ets-1 and NF kappa B to their respective enhancer elements found in MMP-3 promoter. In summary, our results indicated that TNF alpha enhances the invasiveness of T98G glioma cells through MMP-3 induction, and such enhancement of cell migration can be inhibited by IFN gamma. (c) 2007 Wiley-Liss, Inc.