Role of protein kinase C activity in tumor necrosis factor-α gene expression: Involvement at the transcriptional level

Il Yup Chung, Jongbum Kwon, Etty N. Benveniste

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69 Scopus citations

Abstract

Primary rat astrocytes express TNF-α protein in response to various stimuli including a combined treatment with IFN-γ and LPS, or IFN-γ and IL-1β. This study was undertaken to further elucidate the mechanisms underlying TNF-α gene expression in the astrocyte, and to determine the intracellular signaling pathways involved in IFN-γ/LPS and/or IFN-γ/IL-1β induction of the TNF-α gene. We demonstrate that TNF-α mRNA is rapidly induced, and mRNA levels peak after 2 h of stimulation. De novo protein synthesis is not required for TNF-α expression because the inclusion of cycloheximide does not prevent expression of the gene and acts to superinduce TNF-α mRNA levels. IFN-γ/LPS induces transcriptional activation of the TNF-α gene as assessed by nuclear run-on experiments. Cycloheximide acts to increase both transcription of the TNF-α gene and stability of TNF-α mRNA thereby resulting in increased TNF-α steady state mRNA levels. Two protein kinase C (PKC) inhibitors, H7 and staurosporine, abrogate IFN-γ/LPS- and IFN-γ/IL-1β-induced TNF-α expression in a dose-dependent manner. PKC activity is required for transcription of the TNF-α gene, and does not appear to be involved in TNF-α mRNA stabilization. Taken together, these data demonstrate that TNF-α gene expression in primary rat astrocytes is induced in a PKC-dependent manner.

Original languageEnglish
Pages (from-to)3894-3902
Number of pages9
JournalJournal of Immunology
Volume149
Issue number12
StatePublished - 1992

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