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Cited by 326Advanced Glycation End Products researchNF-κB Signaling PathwaysImmune Response and Inflammation

Requirement for p38 and p44/p42 Mitogen-Activated Protein Kinases in RAGE-Mediated Nuclear Factor-κB Transcriptional Activation and Cytokine Secretion

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Yeh, Chen-Hsiung, Sturgis, Lydia, Haidacher, Joe, Zhang, Xue-Nong, Sherwood, Sidney J., Bjercke, Robert J., Juhasz, Ondrej, Crow, Michael T. +2 more·2001·Diabetes
DOI 10.2337/diabetes.50.6.1495
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Abstract

Advanced glycation end product (AGE) activation of the signal-transducing receptor for AGE (RAGE) has been linked to a proinflammatory phenotypic change within cells. However, the precise intracellular signaling pathways involved have not been elucidated. We demonstrate here that human serum albumin modified with Nε-(carboxymethyl)lysine (CML), a major AGE adduct that progressively accumulates with aging, diabetes, and renal failure, induced nuclear factor (NF)-κB–driven reporter gene expression in human monocytic THP-1 cells. The NF-κB response was blocked with a synthetic peptide corresponding to the putative ligand-binding domain of RAGE, with anti-RAGE antiserum, and by coexpression of truncated receptors lacking the intracellular domain. Signal transduction from RAGE to NF-κB involved the generation of reactive oxygen species, since reporter gene expression was blocked with the antioxidant N-acetyl-l-cysteine. CML-modified albumin produced rapid transient activation of tyrosine phosphorylation, extracellular signal-regulated kinase 1 and 2, and p38 mitogen-activated protein kinase (MAPK), but not c-Jun NH2-terminal kinase. RAGE-mediated NF-κB activation was suppressed by the selective p38 MAPK inhibitor SB203580 and by coexpression of a kinase-dead p38 dominant-negative mutant. Activation of NF-κB by CML-modified albumin increased secretion of proinflammatory cytokines (tumor necrosis factor-α, interleukin-1β, and monocyte chemoattractant protein-1) severalfold, and inhibition of p38 MAPK blocked these increases. These results indicate that p38 MAPK activation mediates RAGE-induced NF-κB–dependent secretion of proinflammatory cytokines and suggest that accelerated inflammation may be a consequence of cellular activation induced by this receptor.

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  • AGEs activate the ERK, JNK, p38, and PI3K pathways and promote activation of NF-κB.

    “AGEs activate the ERK, c-Jun N-terminal kinase (JNK), p38, and PI3K pathways and promote activation of NF-κB.”

    From The Vasculature in Prediabetes (2018) · cites this paper as [58]

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Research works printed but not linked: 1

  1. Coligan JE, Kruisbeek AM, Margulies DH, Shevach EM, Strober W, Eds. New York, Greene Publishing and John Wiley & Sons, p. 7.1.1-7.1.7, 1996

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Authors
Yeh, C.-H., Sturgis, L., Haidacher, J., Zhang, X.-N., Sherwood, S. J., Bjercke, R. J., Juhasz, O., Crow, M. T., Tilton, R. G., & Denner, L.
Affiliations
  • Cell Biology and Apoptosis Program and the
  • Department of Immunology, Texas Biotechnology Corporation, Houston, Texas
  • Laboratory of Cardiovascular Science, National Institute on Aging, National Institutes of Health, Baltimore, Maryland
  • National Institutes of Health (US)
ORCID
Tilton, Ronald G.
Venue
Diabetes
Publisher
American Diabetes Association
Published
2001-06-01
Volume
50
Issue
6
Pages
1495-1504
ISSN
  • 0012-1797 (ISSN-L)
  • 1939-327X
DOI
10.2337/diabetes.50.6.1495
OpenAlex
W2126160998
Cited by
326
References
65
Citations by year
2026: 1 · 2025: 4 · 2024: 6 · 2023: 5 · 2022: 11 · 2021: 15 · 2020: 8 · 2019: 5 · 2018: 4 · 2017: 14 · 2016: 11 · 2015: 13 · 2014: 7 · 2013: 29 · 2012: 15
FWCI
10.15
Type
journal article
Language
en
Open access
Locations
  • Diabetes (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Advanced Glycation End Products research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
  • Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
Keywords
receptor for advanced glycation end products, RAGE, p38 MAPK, ERK1/2, advanced glycation end products, reactive oxygen species, proinflammatory cytokine secretion, TNF-α, IL-1β, MCP-1, THP-1 cells, inflammation
MeSH terms
Receptor for Advanced Glycation End Products, Cell Line, Enzyme Activation, Multigene Family, Humans, Lysine, Monocytes, Phosphorylation, Protein-Tyrosine Kinases, Receptors, Immunologic, Transcription, Genetic, Tyrosine, Signal Transduction, Transcriptional Activation, Cytokines, NF-kappa B, Reactive Oxygen Species, Mitogen-Activated Protein Kinase 1, Mitogen-Activated Protein Kinases, p38 Mitogen-Activated Protein Kinases, Mitogen-Activated Protein Kinase 3

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