Requirement for p38 and p44/p42 mitogen-activated protein kinases in RAGE-mediated nuclear factor-κB transcriptional activation and cytokine secretion

Chen Hsiung Yeh, Lydia Sturgis, Joe Haidacher, Xue Nong Zhang, Sidney J. Sherwood, Robert J. Bjercke, Ondrej Juhasz, Michael T. Crow, Ronald G. Tilton, Larry Denner

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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.

Original languageEnglish (US)
Pages (from-to)1495-1504
Number of pages10
JournalDiabetes
Volume50
Issue number6
DOIs
StatePublished - Jan 1 2001

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ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

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. (2001). Requirement for p38 and p44/p42 mitogen-activated protein kinases in RAGE-mediated nuclear factor-κB transcriptional activation and cytokine secretion. Diabetes, 50(6), 1495-1504. https://doi.org/10.2337/diabetes.50.6.1495