BMC Genomics. 2003 Nov 25
Schwamborn J, Lindecke A, Elvers M, Horejschi V, Kerick M, Rafigh M, Pfeiffer J, Pruellage M, Kaltschmidt B, Kaltschmidt C.
Tumor necrosis factor alpha (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 1h up to 12 h post TNF treatment in comparison to untreated U373 cells.
TNF activated strongly the NF-kB transcriptional pathway and is linked to other pathways via the NF-kB target genes JUNB and IRF-1.
Part of the TNF-induced gene expression could be inhibited by pharmacological inhibition of NF-kB with pyrrolidine-dithiocarbamate (PDTC).
NF-kB comprises a family of transcription factors which are involved in the inducible expression of genes regulating neuronal survival, inflammatory response, cancer and innate immunity.
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-kB in astroglia: Activation of NF-kB 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.
The vast majority of genes regulated more than 3-fold were previously not linked to tumor necrosis factor alpha as a search in published literature revealed.
Striking co-regulation for several functional groups such as proteasome and ribosomal proteins were detected.