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.
Background:
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.
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-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.
Conclusions:
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.