Journal of Lipid Research, Vol 35, 1413-1421, Copyright © 1994 by Lipid Research, Inc.

ARTICLES

Induction of tumor necrosis factor alpha gene expression by lipoprotein lipase requires protein kinase C activation

G Reiner, M Oliver, E Skamene and D Radzioch
Department of Nutrition, Notre-Dame Hospital Research Center, Montreal, Canada.

We have previously found that lipoprotein lipase (LPL) induces tumor necrosis factor alpha (TNF alpha) mRNA expression and TNF alpha protein production in the ANA-1 macrophage cell line and in resident murine macrophages. The present study was designed to elucidate the intracellular signalling pathways involved in the LPL-induced TNF alpha gene expression. Treatment of macrophages with two protein kinase C (PKC) inhibitors, 1-(5-isoquinolinesulfonyl)-2-methylpiperazine hydrochloride (H7) and calphostin C, suppressed LPL-induced TNF alpha mRNA expression and protein production. In contrast, no inhibition of the TNF alpha mRNA expression occurred when macrophages were exposed to an inhibitor of calmodulin-dependent kinase N-(6-amino-hexyl)-5-chloro- 1-naphthalene-sulfonamide hydrochloride (W7). Overnight treatment of ANA-1 cells with 100 ng/ml 4 beta-phorbol 12 beta-myristate 13 alpha- acetate (PMA) caused the suppression of both PKC activity and LPL- induced TNF alpha mRNA expression. We have also found that LPL treatment increased PKC activity in macrophages and induced a translocation of this enzyme from the cytosol to the membrane. Finally, we have demonstrated that H7 inhibited the enhancement of nuclear protein binding to the NFkB consensus sequence in the promoter of the TNF alpha gene that we observed in LPL-treated macrophages. Moreover, the treatment of macrophages with H7 abolished the stabilization of TNF alpha mRNA in response to LPL. Overall these data demonstrate that LPL induces TNF alpha mRNA expression in a PKC-dependent manner and that the PKC effect involves transcriptional events as well as posttranscriptional modifications.
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