IntroductionAIDS is characterized by a profound reduction of CD4 ϩ T lymphocytes, immune defects, and cytokine dysregulation, leading to opportunistic infections and tumorgenesis. 1 HIV-1 has been identified to be the primary etiologic agent. Among HIV-1 gene products, transactivator protein (Tat) is required for efficient viral gene expression by interacting with the HIV long terminal repeat to enhance transcription and RNA processing. 2 Apart from its effects on viral replication, Tat is secreted extracellularly by the infected cells and exerts its paracrine effects on neighboring cells. 3 It has been shown that extracellular Tat may play a diverse role in dysregulating the host immune response via the modulation of cellular gene expression. 4 For example, previous reports including ours showed Tat induces the overexpression of interleukin-10 (IL-10), which is a well known immunosuppressive cytokine capable of down-regulating TH1 cell function and IL-2 synthesis. 5 We recently demonstrated Tat induces IL-10 expression via cellular kinase PKR activity and the activation of transcription factor Ets-1. 6,7 PKR, one of the key genes in the mediation of interferoninduced activities, is a prototype kinase modulated by Tat in HIV-1 perturbation of the cytokine systems. 8 Infection with HIV-1 marks the onset of changes in the microenvironment of the host cell. Throughout all stages of HIV-1 infection, chronic immune activation and dysfunctional cytokine production have been observed. 9 Soluble mediators, including cytokines and viral products such as Tat, produced by the infected cells may enhance the progression of HIV-1 infection either by direct effects or through deregulation of cytokine expression such as interferon-␥ (IFN␥) and tumor necrosis factor-␣ (TNF␣). 7,10 Therefore, elucidating the transcriptional regulation of host genes including cytokines and their regulated pathways upon HIV-1 viral protein stimulation can be used as a tool to delineate the mechanisms of host-virus interactions, and to understand the molecular basis of AIDS pathogenesis.Interferon-␥ is a pleiotropic cytokine produced primarily by T lymphocytes and natural killer (NK) cells in response to viral infection. It is an important mediator with multiple biological activities including macrophage activation, and antimicrobial, antiproliferative, and immunomodulatory effects. 11 It has been shown that IFN␥ receptor-deficient mice are significantly impaired in their abilities to resist infection by microbes including virus, bacteria, and protozoa. 12 Central to IFN␥-induced cellular responses is the activation of Janus kinase-1 (Jak1) and Jak2 and consequent phosphorylation of STAT1. The phosphorylated STAT1 (pSTAT1) undergoes dimerization and translocation into the nucleus, where it binds to IFN␥-activated sequence (GAS) elements present in the promoter of IFN␥-regulated genes, and consequently leads to initiation of transcription. 13 Previous studies of IFN-induced signaling cascade suggested overexpression of suppressor of cytokine signalin...

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)a-resistant glioblastoma, whose growth is associated with TNFa expression. We thus examined whether the tumor takes advantage of TNFa 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-c (IFNc) reduced both basal and TNFa-enhanced cell invasion. To investigate the mechanisms involved, we demonstrated that TNFa upregulated mRNA and protein expression of MMP-3 in T98G cells, whereas IFNc 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 TNFa-enhanced cell invasion. To delineate the mechanisms further, we showed that IFNc exerts an inhibitory effect on the binding of TNFa-activated Ets-1 and NFjB to their respective enhancer elements found in MMP-3 promoter. In summary, our results indicated that TNFa enhances the invasiveness of T98G glioma cells through MMP-3 induction, and such enhancement of cell migration can be inhibited by IFNc. ' 2007 Wiley-Liss, Inc.Key words: MMP-3; IFNc; TNFa; invasiveness; glioma Glioblastoma is a malignant and highly invasive form of astrocyte-derived brain tumor, which accounts for more than 40% of all central nervous system neoplasm.1 Because of its relative resistance to radiation and chemotherapy, the prognosis for malignant glioblastoma remains poor.2 In addition, most of glioblastoma cells are resistant to tumor necrosis factor (TNF)-induced cytotoxic effects 3 and high invasiveness of these tumor cells makes the complete surgical resection nearly impossible in most cases. Glioblastoma consists of both neoplastic cells (glioma) and non-neoplastic cellular elements including fibroblasts, endothelial cells, lymphocytes and macrophages surrounded by extracellular matrix.4 During tumor development, changes in the milieu provoke cytokine expression, which in turn stimulates leukocyte infiltration leading to the release of more cytokines.Induction of proinflammatory cytokines in various preneoplastic and malignant diseases is commonly believed to be the host immune response against tumor development and progression. However, growing evidences have suggested that inflammation is actually an indispensable participant in the neoplastic process, nurturing proliferation, survival and migration of cancer cells. 5,6 Therefore, within this microenvironment, cytok...

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