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Lipopolysaccharide-mediated Reactive Oxygen Species and Signal Transduction in the Regulation of Interleukin-1 Gene Expression
Open accessAbstract
Lipopolysaccharide (LPS) stimulates macrophages to release inflammatory cytokines, interleukin-1 beta (IL-1), and tumor necrosis factor (TNF). LPS-induced TNF suppresses scavenger receptor functions in macrophages (van Lenten, B. J., and Fogelman, A. M. (1992) J. Immunol. 148, 112-116), which is regulated by TNF-mediated protein kinases (Hsu, H. Y., and Twu, Y. C. (2000) J. Biol. Chem. 275, 41035-41048). To examine the molecular mechanism for LPS induction of IL-1 in macrophages, we demonstrated that LPS quickly stimulated reactive oxygen species (ROS), and 3 h later induced prointerleukin-1 beta (pro-IL-1, precursor of IL-1) production and IL-1 secretion. LPS stimulated pro-IL-1 message/protein between 3 and 10 h; however, there was a 40% reduction of pro-IL-1 in preincubation of the antioxidant, N-acetylcysteine (NAC). Moreover, NAC moderated LPS-induced IL-1 secretion partially via interleukin 1-converting enzyme. The maximal activity of LPS-induced ERK, JNK, and p38 was 12- (30 min), 5- (30 min), and 16-fold (15 min), respectively. In contrast, NAC reduced ERK activity to 60% and decreased p38 activity to the basal level, but JNK activity was induced 2-fold. Furthermore, the pharmacological antagonists LY294002, SB203580, curcumin, calphostin C, and PD98059 revealed the diverse roles of LPS-mediated protein kinases in pro-IL-1. On the other hand, NAC and diphenyleneiodonium chloride partially inhibited LPS-induced Rac activity and protein-tyrosine kinase (PTK), indicating that LPS-mediated ROS and NADPH oxidase correspond to Rac activation and IL-1 expression. Our findings establish for the first time that LPS-mediated PTK/phosphatidylinositol 3-kinase/Rac/p38 pathways play a more important role than pathways of PTK/PKC/MEK/ERK and of PTK/phosphatidylinositol 3-kinase/Rac/JNK in the regulation of pro-IL-1/IL-1. The findings also further elucidate the critical role of LPS-mediated ROS in signal transduction pathways. Our results suggest that understanding LPS-transduced signals in IL-1 induction upon the antibacterial action of macrophages should provide a therapeutic strategy for aberrant inflammatory responses leading to severe cellular injury or concurrent multiorgan septic damage.
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“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 [2027]
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“…the interleukin-1 converting enzyme, in which NAC reduces the conversion of interleukin-1β (inactive form of the cytokine) to its active form (Hsu and Wen 2002) Studies have already shown that, in addition to its antioxidant and anti-inflammatory effects, NAC also influences the expression…”
Bhunyakarnjanarat, T., Suksamai, C., Somsri, K., Kowitwibool, K., Haripottawekul, N., Wannigama, D. L., Doi, K., Chancharoenthana, W., & Leelahavanichkul, A. (2026) · International Immunopharmacology · doi:10.1016/j.intimp.2026.116875
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The Role of Skeletal Muscle Mitochondria in NLRP3 Inflammasome Signaling
Sangha, J., & Hood, D. A. (2026) · Biomolecules · doi:10.3390/biom16081218
“In addition, LPS stimulation itself promotes cellular ROS levels [142,143] and activates the inflammasome, while blunting mtROS levels improved myotube diameter [58].”
Dabrafenib Alleviates the Effects of Lipopolysaccharides in Endothelial Cells
Fakir, S., Sarker, M. M. R., Sigdel, M., & Barabutis, N. (2026) · Drug Research · doi:10.1055/a-2965-5307
Metadata
- Authors
- Hsu, H.-Y., & Wen, M.-H.
- Affiliations
- National Yang Ming University (TW)
- Corresponding author
- Hsu, Hsien-Yeh
- ORCID
- Wen, Meng-Hsuan
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2002-06
- Volume
- 277
- Issue
- 25
- Pages
- 22131-22139
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2016146035
- Cited by
- 519
- References
- 72
- Citations by year
- 2026: 13 · 2025: 17 · 2024: 20 · 2023: 21 · 2022: 21 · 2021: 27 · 2020: 22 · 2019: 23 · 2018: 25 · 2017: 33 · 2016: 27 · 2015: 21 · 2014: 18 · 2013: 19 · 2012: 14
- FWCI
- 7.22
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
- Keywords
- lipopolysaccharide, IL-1β, reactive oxygen species, N-acetylcysteine, macrophages, Rac, p38 MAPK, JNK, ERK, phosphatidylinositol 3-kinase, tyrosine kinase, NADPH oxidase, signal transduction, inflammatory cytokines, TNF-α
- MeSH terms
- Animals, Carrier Proteins, Cell Line, Chromones, Curcumin, Enzyme Activation, Enzyme Inhibitors, Enzyme-Linked Immunosorbent Assay, Flavonoids, Gene Expression Regulation, Genes, Dominant, Imidazoles, Interleukin-1, Lipopolysaccharides, Macrophages, Models, Biological, Morpholines, Naphthalenes, Oxygen, Protein Binding, Pyridines, Time Factors, Transfection, Signal Transduction, Reactive Oxygen Species, rac1 GTP-Binding Protein, Mitogen-Activated Protein Kinases, Mitogen-Activated Protein Kinase Kinases, Intracellular Signaling Peptides and Proteins, JNK Mitogen-Activated Protein Kinases, p38 Mitogen-Activated Protein Kinases, MAP Kinase Kinase 4, Mice
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