The Phosphatidylinositol 3-Kinase-Akt Pathway Limits Lipopolysaccharide Activation of Signaling Pathways and Expression of Inflammatory Mediators in Human Monocytic Cells*

By M. Guha, N. Mackman. Journal of Biological Chemistry, 2002

865 citations recorded by the source corpus.

Monocytes and macrophages express cytokines and procoagulant molecules in various inflammatory diseases. In sepsis, lipopolysaccharide (LPS) from Gram-negative bacteria induces tumor necrosis factor-alpha (TNF-α) and tissue factor (TF) in monocytic cells via the activation of the transcription factors Egr-1, AP-1, and nuclear factor-κB. However, the signaling pathways that negatively regulate LPS-induced TNF-α and TF expression in monocytic cells are currently unknown. We report that inhibition of the phosphatidylinositol 3-kinase (PI3K)-Akt pathway enhances LPS-induced activation of the mitogen-activated protein kinase pathways (ERK1/2, p38, and JNK) and the downstream targets AP-1 and Egr-1. In addition, inhibition of PI3K-Akt enhanced LPS-induced nuclear translocation of nuclear factor-κB and prevented Akt-dependent inactivation of glycogen synthase kinase-β, which increased the transactivational activity of p65. We propose that the activation of the PI3K-Akt pathway in human monocytes limits the LPS induction of TNF-α and TF expression. Our study provides new insight into the inhibitory mechanism by which the PI3K-Akt pathway ensures transient expression of these potent inflammatory mediators.

Subfields: Immunology, Molecular Biology, Surgery

View Paper: https://www.semanticscholar.org/paper/f7150c4cb1c0f8525def941e0548ab7a5f7a5b58

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Citations in the corpus

Akt Signaling Pathway in Macrophage Activation and M1/M2 Polarization (2017, background): “PI3K, the upstream regulator of Akt, is shown to mediate M2 macrophage phenotypes (19, 23, 40).”
AMP-activated protein kinase promotes macrophage polarization to an anti-inflammatory functional phenotype (2008, positive): “The PI3K/Akt pathway has been shown to regulate the production of inflammatory cytokines in monocytes and macrophages (27), and inhibition of GSK3- has been shown to inhibit TLR-mediated production of proinflammatory cytokines, while enhancing IL-10 production by human monocytes (27, 28).”
Akt1 controls macrophage response to LPS by regulating microRNAs (2009, background): “Thus, activation of the PI-3K-Akt pathway suppresses LPS-activated MAPK and NF-kB signaling cascades in monocytes and dendritic cells, resulting in decreased production of TNF-a and other cytokines (Fukao et al., 2002; Guha and Mackman, 2002).”
Toll-like receptor–mediated cytokine production is differentially regulated by glycogen synthase kinase 3 (2005, background): “to limit production of tumor necrosis factor (TNF) and interleukin 12 (IL-12”
The complexity of NF-κB signaling in inflammation and cancer (2013, background): “This has been reported for instance for the influence of Akt on NF-κB, which is activating in cell types such as epithelial cells, but can be inhibitory in macrophages [137-140].”