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Diabetes 54:85-91, 2005
© 2005 by the American Diabetes Association, Inc.

Hyperglycemia Induces Monocytic Release of Interleukin-6 via Induction of Protein Kinase C-{alpha} and -ß

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

Laboratory for Atherosclerosis and Metabolic Research, Department of Pathology, University of California Davis Medical Center, Sacramento, California

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-{alpha}/ß2 inhibitor decreased p38MAPK and the resulting high-glucose–induced IL-6 release. Both antisense oligos to PKC-ß and -{alpha} as well as small interfering RNA (siRNA) to PKC-{alpha} and -ß resulted in significantly decreased high-glucose–induced IL-6 release. Nuclear factor-{kappa}B (NF-{kappa}B) inhibitors significantly decreased IL-6 mRNA and protein. siRNA to PKC-ß and -{alpha} also significantly decreased NF-{kappa}B 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-{kappa}B, resulting in increased mRNA and protein for IL-6. Thus, inhibition of PKC-{alpha} and -ß can ameliorate the proinflammatory state of diabetes.

Address correspondence and reprint requests to I. Jialal, MD, PhD, Director, Laboratory for Atherosclerosis and Metabolic Research, the University of California Davis Medical Center, 4635, II Ave., Res. 1 Bldg., Rm. 3000, Sacramento, CA 95817. E-mail: ishwarlal.jialal{at}ucdmc.ucdavis.edu


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