High glucose induces toll-like receptor expression in human monocytes Mechanism of activation

Mohan R. Dasu, Sridevi Devaraj, Ling Zhao, Daniel H. Hwang, Ishwarlal Jialal

Research output: Contribution to journalArticle

298 Scopus citations

Abstract

OBJECTIVE-Hyperglycemia-induced inflammation is central in diabetes complications, and monocytes are important in orchestrating these effects. Toll-like receptors (TLRs) play a key role in innate immune responses and inflammation. However, there is a paucity of data examining the expression and activity of TLRs in hyperglyce- mic conditions. Thus, in the present study, we examined TLR2 and TLR4 mRNA and protein expression and mechanism of their induction in monocytic cells under high-glucose conditions. RESEARCH DESIGN AND METHODS-High glucose (15 mmol/l) significantly induced TLR2 and TLR4 expression in THP-1 cells in a time- and dose-dependent manner (P < 0.05). High glucose increased TLR expression, myeloid differentiation factor 88, interleukin-1 receptor-associated kinase-1, and nuclear factor-κB (NF- κB) p65-dependent activation in THP-1 cells. THP-1 cell data were further confirmed using freshly isolated monocytes from healthy human volunteers (n = 10). RESULTS-Pharmacological inhibition of protein kinase C (PKC) activity and NADPH oxidase significantly decreased TLR2 and TLR4 mRNA and protein (P < 0.05). Knocking down both TLR2 and TLR4 in the cells resulted in a 76% (P < 0.05) decrease in high-glucose-induced NF-κB activity, suggesting an additive effect. Furthermore, PKC-α knockdown decreased TLR2 by 61% (P < 0.05), whereas inhibition of PKC-δ decreased TLR4 under high glucose by 63% (P < 0.05). Small inhibitory RNA to p47Phox in THP-1 cells abrogated high-glucose-induced TLR2 and TLR4 expression. Additional studies revealed that PKC-α, PKC-δ, and p47Phox knockdown significantly abrogated high-glucose-induced NF-κB activation and inflammatory cytokine secretion. CONCLUSIONS-Collectively, these data suggest that high glucose induces TLR2 and -4 expression via PKC-α and PKC-δ, respectively, by stimulating NADPH oxidase in human monocytes.

Original languageEnglish (US)
Pages (from-to)3090-3098
Number of pages9
JournalDiabetes
Volume57
Issue number11
DOIs
StatePublished - Nov 2008

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

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    Dasu, M. R., Devaraj, S., Zhao, L., Hwang, D. H., & Jialal, I. (2008). High glucose induces toll-like receptor expression in human monocytes Mechanism of activation. Diabetes, 57(11), 3090-3098. https://doi.org/10.2337/db08-0564