TITLE

Microarray analysis of tumor necrosis factor α induced gene expression in U373 human glioblastoma cells

AUTHOR(S)
Schwamborn, Jens; Lindecke, Antje; Elvers, Margitta; Horejschi, Volker; Kerick, Martin; Rafigh, Mehran; Pfeiffer, Julia; Prüllage, Maria; Kaltschmidt, Barbara; Kaltschmidt, Christian
PUB. DATE
January 2003
SOURCE
BMC Genomics;2003, Vol. 4, p46
SOURCE TYPE
Academic Journal
DOC. TYPE
Article
ABSTRACT
Background: Tumor necrosis factor a (TNF) is able to induce a variety of biological responses in the nervous system including inflammation and neuroprotection. Human astrocytoma cells U373 have been widely used as a model for inflammatory cytokine actions in the nervous system. Here we used cDNA microarrays to analyze the time course of the transcriptional response from 1 h up to 12 h post TNF treatment in comparison to untreated U373 cells. TNF activated strongly the NF-κB transcriptional pathway and is linked to other pathways via the NF-κB target genes JUNB and IRF-1. Part of the TNF-induced gene expression could be inhibited by pharmacological inhibition of NF-?B with pyrrolidine-dithiocarbamate (PDTC). NF-κB comprises a family of transcription factors which are involved in the inducible expression of genes regulating neuronal survival, inflammatory response, cancer and innate immunity. Results: In this study we show that numerous genes responded to TNF (> 880 from 7500 tested) with a more than two-fold induction rate. Several novel TNF-responsive genes (about 60% of the genes regulated by a factor ≥ 3) were detected. A comparison of our TNF-induced gene expression profiles of U373, with profiles from 3T3 and Hela cells revealed a striking cell-type specificity. SCYA2 (MCP-1, CCL2, MCAF) was induced in U373 cells in a sustained manner and at the highest level of all analyzed genes. MCP-1 protein expression, as monitored with immunofluorescence and ELISA, correlated exactly with microarray data. Based on these data and on evidence from literature we suggest a model for the potential neurodegenerative effect of NF-κB in astroglia: Activation of NF-κB via TNF results in a strongly increased production of MCP-1. This leads to a exacerbation of neurodegeneration in stoke or Multiple Sclerosis, presumably via infiltration of macrophages. Conclusions: The vast majority of genes regulated more than 3-fold were previously not linked to tumor necrosis factor a as a search in published literature revealed. Striking co-regulation for several functional groups such as proteasome and ribosomal proteins were detected.
ACCESSION #
28834605

 

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