Hyperglycemia induces monocytic release of interleukin-6 via induction of protein kinase C-α and -β

Sridevi Devaraj, Senthil K. Venugopal, Uma Singh, Ishwarlal Jialal

Research output: Contribution to journalArticle

151 Citations (Scopus)

Abstract

Diabetes confers an increased propensity to atherosclerosis. Inflammation is pivotal in atherogenesis, and diabetes is a proinflammatory state. Interleukin (IL)-6, in addition to inducing the acute-phase response, contributes to insulin resistance. Monocytes from type 2 diabetic patients secrete increased IL-6. The aim of this study was to examine molecular mechanisms for increased IL-6 release from monocytes under hyperglycemia. Monocytic cells (THP-1) were cultured in the presence of 5.5 mmol/l (normal) or 15 mmol/l (high) glucose and mannitol. Secreted IL-6, intracellular IL-6, and IL-6 mRNA were significantly increased with hyperglycemia (P < 0.001). Incubation of cells with inhibitors of reactive oxygen species failed to affect high-glucose-induced IL-6 release. Pan-protein kinase C (PKC) inhibitors significantly decreased high-glucose-induced IL-6 release. A specific inhibitor of p38 mitogen-activated protein kinase (MAPK; SB 202190), but not the extracellular signal-regulated kinase inhibitor PD98059, significantly decreased high-glucose-induced IL-6 release. Furthermore, the PKC-α/β2 inhibitor decreased p38MAPK and the resulting high-glucose-induced IL-6 release. Both antisense oligos to PKC-β and -α as well as small interfering RNA (siRNA) to PKC-α and -β resulted in significantly decreased high-glucose-induced IL-6 release. Nuclear factor-κB (NF-κB) inhibitors significantly decreased IL-6 mRNA and protein. siRNA to PKC-β and -α also significantly decreased NF-κB activity and IL-6 release. The combination was not additive to either siRNA alone, suggesting that they work through a common pathway. Thus, IL-6 release from monocytes under hyperglycemia appears to be mediated via upregulation of PKC, through p38MAPK and NF-κB, resulting in increased mRNA and protein for IL-6. Thus, inhibition of PKC-α and -β can ameliorate the proinflammatory state of diabetes.

Original languageEnglish (US)
Pages (from-to)85-91
Number of pages7
JournalDiabetes
Volume54
Issue number1
DOIs
StatePublished - Jan 2005

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Hyperglycemia
Protein Kinase C
Interleukin-6
Glucose
Small Interfering RNA
Monocytes
Messenger RNA
Atherosclerosis
Acute-Phase Reaction
Protein C Inhibitor
Extracellular Signal-Regulated MAP Kinases
Mannitol
p38 Mitogen-Activated Protein Kinases
Protein Kinase Inhibitors
Insulin Resistance
Reactive Oxygen Species
Proteins
Up-Regulation

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

Hyperglycemia induces monocytic release of interleukin-6 via induction of protein kinase C-α and -β. / Devaraj, Sridevi; Venugopal, Senthil K.; Singh, Uma; Jialal, Ishwarlal.

In: Diabetes, Vol. 54, No. 1, 01.2005, p. 85-91.

Research output: Contribution to journalArticle

Devaraj, Sridevi ; Venugopal, Senthil K. ; Singh, Uma ; Jialal, Ishwarlal. / Hyperglycemia induces monocytic release of interleukin-6 via induction of protein kinase C-α and -β. In: Diabetes. 2005 ; Vol. 54, No. 1. pp. 85-91.
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