Phosphatidylinositol 3-Kinase as a Mediator of TNF-Induced NF-κB Activation

Abstract

The activation of transcription factor NF-κB by TNF involves the stimulation of a novel signaling cascade. In this paper we show that phosphatidylinositol 3-kinase (PI 3-kinase) may play a pivotal role in TNF-mediated activation of NF-κB-dependent genes. Consistent with its involvement in TNF signaling, PI 3-kinase activities in HepG2 and U937 cells can be stimulated by TNF in a rapid but transient manner through a mechanism that may involve its association with the insulin receptor substrate-1. A dominant-negative mutant of the p85 regulatory subunit of PI 3-kinase, which is a potent inhibitor of PI 3-kinase signaling, effectively blocked the TNF-induced expression of an NF-κB-dependent reporter gene. Although PI 3-kinase may be required for NF-κB activation, overexpression of its p110 catalytic subunit alone was unable to induce an NF-κB/chloramphenicol acetyltransferase (CAT) reporter gene. However, when TNF was added to p110-overexpressing cells, there was a synergistic activation of the NF-κB/CAT reporter, suggesting that other TNF-inducible signals may cooperate with PI 3-kinase to activate NF-κB. Consistent with its role in NF-κB activation, inhibition of PI 3-kinase activity by wortmannin or LY294002 greatly potentiated TNF-induced apoptosis. This TNF/wortmannin-induced apoptosis was markedly prevented in cells overexpressing Rel A. Taken together, our results indicate that a PI 3-kinase-regulated step in TNF-signaling is critical for the expression of NF-κB-dependent genes.

The Fas-FasL death receptor and PI3K pathways independently regulate monocyte homeostasis

“…PI3K regulates multiple pathways monocyte activity [11,[15][16][17][18][19][20][21][22][23][24][25][26][27]. PI3K is necessary for monocyte survival, since inhibition of PI3K and subsequently Akt resulted in cell death even in the presence of LPS or TNF- § .…”

“…Previous studies have suggested that Akt may inhibit apoptosis mediated by the death receptor or mitochondrial pathways, through the phosphorylation and inactivation of the pro-apoptotic Bcl-2 family protein Bad, caspase 9 or the forkhead transcription factor [12]. Furthermore, Akt was also shown to activate NF-‹ B and suppress apoptosis through an unknown mechanism [16], although recent investigations suggested that NK-‹ B regulation by PI3K/Akt pathway may be cell type specific [28]. Thus, the mechanism by which the mitochondrial apoptotic pathway may be regulated by PI3K in monocytes is unclear.…”

1,25(OH)2D3 blocks TNF-induced monocytic tissue factor expression by inhibition of transcription factors AP-1 and NF-κB

“…7 A recent study demonstrated that PI3K-Akt may play a pivotal role in cytokine-induced transcriptional activation of NF-kB-and AP-1-dependent gene expression. 8,9 The active form of vitamin D 3 , 1a,25-dihydroxyvitamin D 3 (1,25(OH) 2 D 3 ), influences the expression of various genes, whose products are involved in calcium homeostasis, cell differentiation, and regulation of the immune response. 10 The expression of these genes is mediated by binding to its nuclear vitamin D receptor (VDR), a transcription factor, which dimerizes with either itself or other nuclear receptors, such as the retinoid X receptor (RXR).…”

Reduction of Potassium Currents and Phosphatidylinositol 3-Kinase-Dependent Akt Phosphorylation by Tumor Necrosis Factor-α Rescues Axotomized Retinal Ganglion Cells from Retrograde Cell DeathIn Vivo

“…In recent studies, Akt has been identified as a part of the TNF-␣ signaling pathway that leads to inflammatory responses and inhibition of apoptosis in vitro (Nidai Ozes et al, 1999;Pastorino et al, 1999;Reddy et al, 2000). A connection between membrane depolarization and phosphatidylinositol 3-kinase (PI3-K)-dependent Akt phosphorylation was found in cultured rat sympathetic neurons (Vaillant et al, 1999).…”