The Phosphatidylinositol 3-Kinase-Akt Pathway Limits Lipopolysaccharide Activation of Signaling Pathways and Expression of Inflammatory Mediators in Human Monocytic Cells
Open accessAbstract
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-alpha) and tissue factor (TF) in monocytic cells via the activation of the transcription factors Egr-1, AP-1, and nuclear factor-kappa B. However, the signaling pathways that negatively regulate LPS-induced TNF-alpha 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-kappa B and prevented Akt-dependent inactivation of glycogen synthase kinase-beta, 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-alpha 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.
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The PI3K-Akt pathway negatively modulates LPS stimulation via a negative feedback loop important for inflammatory response.
“LPS stimulation is negatively modulated by the phosphatidylinositol 3-kinase (PI3K)-Akt pathway, which creates a negative feedback loop important for modulation of the inflammatory response [206].”
From MicroRNAs as Regulators of Phagocytosis (2022) · cites this paper as [206]
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- Authors
- Guha, M., & Mackman, N.
- Affiliations
- Scripps Research Institute (US)
- Corresponding author
- Mackman, Nigel
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2002-08
- Volume
- 277
- Issue
- 35
- Pages
- 32124-32132
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2010817360
- Cited by
- 799
- References
- 1
- Citations by year
- 2026: 13 · 2025: 13 · 2024: 21 · 2023: 19 · 2022: 21 · 2021: 26 · 2020: 25 · 2019: 31 · 2018: 26 · 2017: 33 · 2016: 39 · 2015: 44 · 2014: 42 · 2013: 46 · 2012: 44
- FWCI
- 11.41
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- National Heart, Lung, and Blood Institute (HL-48872, R01HL048872)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Keywords
- PI3K/Akt signaling, lipopolysaccharide, monocytes, macrophages, TNF-α, tissue factor, procoagulant activity, MAPK signaling, ERK1/2, p38 MAPK, JNK, AP-1, EGR1, nuclear factor-kappaB, sepsis, inflammation
- MeSH terms
- Cell Line, DNA-Binding Proteins, Escherichia coli, Gene Expression Regulation, Humans, Inflammation, Lipopolysaccharides, Monocytes, Proto-Oncogene Proteins, Thromboplastin, Transcription Factors, Transcription, Genetic, Tumor Necrosis Factor-alpha, Zinc Fingers, Protein Serine-Threonine Kinases, Immediate-Early Proteins, Transcription Factor AP-1, Phosphatidylinositol 3-Kinases, Proto-Oncogene Proteins c-akt, Early Growth Response Protein 1
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