Interleukin‐1β induction of TNF‐α gene expression: Involvement of protein kinase C

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Abstract
In the human astroglioma cell line CH235-MG, interleukin-1β (IL-1β) induces transcriptional activation of the tumor necrosis factor-alpha (TNF-α) gene, resulting in expression of TNF-α mRNA and biologically active TNF-α protein. This study was undertaken to elucidate intracellular signaling pathways involved in IL-1β induction of the TNF-α gene. We demonstrated that the protein kinase C (PKC) activator 4β-phorbol 12β-myristate 13α-acetate (PMA) in concert with Ca++ ionophore A23187 induced expression of TNF-α mRNA and protein, whereas an inactive PMA analogue (αPMA) had no effect. Various cyclic nucleotide activators such as 8-Bromo cAMP, cholera toxin, and forskolin had no effect on TNF-α production. Two PKC inhibitors, H7 and staurosporine (SS), abrogated IL-1β induced TNF-α expression in a dose-dependent fashion. Treatment of CH235-MG cells with a high concentration of PMA (1 μM) for an extended period of time (48 h) caused a greater than 90% reduction in total PKC activity. Further strengthening a role for PKC in this cytokine response is the fact that IL-1β was no longer able to induce TNF-α expression in these PKC depleted cells. Last, IL-1β treatment produced an increase of total PKC activity in CH235-MG cells. Taken together, these data demonstrate that IL-1β induces TNF-α gene expression in CH235-MG cells in a PKC-dependent manner.

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