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S-adenosylmethionine attenuates the lipopolysaccharide-induced expression of the gene for tumour necrosis factor alpha.

ABSTRACT: Intracellular deficiency of S-adenosylmethionine (AdoMet) and elevated serum concentrations of tumour necrosis factor alpha (TNF) are hallmarks of toxin-induced liver injury. In these models, the administration of either exogenous AdoMet or antibody/soluble receptor for TNF attenuates the injury. We have demonstrated previously that the administration of exogenous AdoMet to AdoMet-deficient rats attenuated lipopolysaccharide (LPS)-induced liver injury and serum TNF concentrations. Here we report that AdoMet lowered the amount of TNF secreted by LPS-stimulated murine macrophage cells (RAW 264.7) in a dose-dependent manner. The inhibition of TNF release was correlated with changes in the steady-state TNF mRNA concentrations. Changes in TNF mRNA were not due to its altered stability and might have been due to an attenuation of the transcription rate of the TNF gene. The inhibition of TNF release in RAW cells was not mediated by GSH because treatment with AdoMet did not increase intracellular GSH. In addition, N-acetylcysteine, whereas it did increase GSH concentration, had no effect on LPS-stimulated TNF release in these cells. Exogenous AdoMet also attenuated LPS-induced serum TNF levels in normal rats sensitized with lead. Thus AdoMet administration might exert its hepatoprotective effects at least in part by its inhibitory effect on expression of the gene for TNF.

SUBMITTER: Watson WH

PROVIDER: S-EPMC1220431 | biostudies-other | 1999 Aug

REPOSITORIES: biostudies-other

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Project description: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 1 h up to 12 h post TNF treatment in comparison to untreated U373 cells. TNF activated strongly the NF-kappaB transcriptional pathway and is linked to other pathways via the NF-kappaB target genes JUNB and IRF-1. Part of the TNF-induced gene expression could be inhibited by pharmacological inhibition of NF-kappaB with pyrrolidine-dithiocarbamate (PDTC). NF-kappaB 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 > or = 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-kappaB in astroglia: Activation of NF-kappaB 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.

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S-adenosylmethionine attenuates the lipopolysaccharide-induced expression of the gene for tumour necrosis factor alpha.

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