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Cited by 106Protein Kinase Regulation and GTPase SignalingImmune Response and InflammationNF-κB Signaling Pathways

Antisense Oligonucleotides Targeting Protein Kinase C-α, -βI, or -δ But Not -η Inhibit Lipopolysaccharide-Induced Nitric Oxide Synthase Expression in RAW 264.7 Macrophages: Involvement of a Nuclear Factor κB-Dependent Mechanism

Chen, Ching-Chow, Wang, Jia-Kae, Lin, Shwu-Bin·1998·The Journal of Immunology
DOI 10.4049/jimmunol.161.11.6206
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Abstract

The signaling pathway for protein kinase C (PKC) activation and the role of PKC isoforms in LPS-induced nitric oxide (NO) release were studied in RAW 264.7 macrophages. The tyrosine kinase inhibitor genestein attenuated LPS-induced NO release and inducible nitric oxide synthase (iNOS) expression, as did the phosphoinositide-specific phospholipase C (PI-PLC) inhibitor U73122 and the phosphatidylcholine-specific phospholipase C (PC-PLC) inhibitor D609. LPS stimulated phosphatidylinositol (PI) hydrolysis and PKC activity in RAW cells; both were inhibited by genestein. The PKC inhibitors (staurosporine, calphostin C, Ro 31-8220, or Go 6976) or long-term 12-O-tetradecanoylphorbol 13-acetate (TPA) treatment also resulted in inhibition of LPS-induced NO release and iNOS expression. Western blot analysis showed expression of PKC-α, -βI, -δ, -η, and -ζ in RAW cells; down-regulation of PKC-α, -βI, and -δ, but not -η, was seen after long-term TPA treatment, indicating the possible involvement of one or all of PKC-α, -βI, and -δ, but not -η, in LPS-mediated effects. Treatment with antisense oligonucleotides for these isoforms further demonstrated the involvement of PKC-α, -βI, and δ, but not -η, in LPS responses. Stimulation of cells with LPS for 1 h caused activation of NF-κB in the nuclei by detection of NF-κB-specific DNA-protein binding; this was inhibited by genestein, U73122, D609, calphostin C, or antisense oligonucleotides for PKC-α, -βI, and -δ, but not -η. These data suggest that LPS activates PI-PLC and PC-PLC via an upstream tyrosine kinase to induce PKC activation, resulting in the stimulation of NF-κB DNA-protein binding, then initiated the expression of iNOS and NO release. PKC isoforms α, βI, and δ were shown to be involved in the regulation of these LPS-induced events.

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  • In the NF-κB system, NF-κB is normally held inactive in the cytoplasm by binding to an inhibitor IκB; pro-inflammatory cytokines such as TNF-α, LPS and IL-1 act by binding to receptors at the cell surface and initiating signalling pathways that lead to activation of IKK; IKK phosphorylates IκB causing its release and degradation, allowing NF-κB to translocate to the nucleus where it can activate a

    “In the NF-κB system (e.g. [2020-2024]) (Fig 8), NF-κB is normally held inactive in the cytoplasm by binding to an inhibitor IκB (often IκBα). Pro-inflammatory cytokines such as TNF-α, LPS [2025-2030] and IL-1 [2031] act by binding to receptors at the cell surface and initiating signalling pathways that lead to the activation of a particular kinase, IκB kinase or IKK. This kinase phosphorylates the”

    From Iron behaving badly: inappropriate iron chelation as a major contributor to the aetiology of vascular and other progressive inflammatory and degenerative diseases (2009) · cites this paper as [2025]

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Authors
Chen, C.-C., Wang, J.-K., & Lin, S.-B.
Affiliations
National Taiwan University (TW)
ORCID
Venue
The Journal of Immunology
Publisher
Oxford University Press (OUP)
Published
1998-12-01
Volume
161
Issue
11
Pages
6206-6214
ISSN
  • 0022-1767 (ISSN-L)
  • 1550-6606
DOI
10.4049/jimmunol.161.11.6206
OpenAlex
W4313344700
Cited by
106
References
50
Citations by year
2023: 2 · 2019: 1 · 2017: 1 · 2016: 3 · 2015: 1 · 2014: 2 · 2013: 4 · 2012: 3
FWCI
3.54
Type
journal article
Language
en
Open access
closed
Licence
academic.oup.com/pages/standard-publication-reuse-rights (vor)
Locations
The Journal of Immunology (publishedVersion)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
  • Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
Keywords
protein kinase C alpha, PKCδ, protein kinase C, lipopolysaccharide, nitric oxide synthase, inducible nitric oxide synthase, macrophages, NF-κB activation, phospholipase C, phosphoinositide hydrolysis, antisense oligonucleotides, tissue plasminogen activator, gene expression regulation, tyrosine kinase signaling

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