Hyperglycemia induces monocytic release of interleukin-6 via induction of protein kinase c-{alpha} and -{beta}.
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/beta2 inhibitor decreased p38MAPK and the resulting high-glucose-induced IL-6 release. Both antisense oligos to PKC-beta and -alpha as well as small interfering RNA (siRNA) to PKC-alpha and -beta resulted in significantly decreased high-glucose-induced IL-6 release. Nuclear factor-kappaB (NF-kappaB) inhibitors significantly decreased IL-6 mRNA and protein. siRNA to PKC-beta and -alpha also significantly decreased NF-kappaB 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-kappaB, resulting in increased mRNA and protein for IL-6. Thus, inhibition of PKC-alpha and -beta can ameliorate the proinflammatory state of diabetes.
Devaraj
Sridevi
S
Laboratory for Atherosclerosis and Metabolic Research, the University of California Davis Medical Center, 4635, II Ave., Res. 1 Bldg., Rm. 3000, Sacramento, CA 95817, USA.
Venugopal
Senthil K
SK
Singh
Uma
U
Jialal
Ishwarlal
I
D002460:Cell Line; D004790:Enzyme Induction; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D006801:Humans; D006943:Hyperglycemia / Q000503:physiopathology*; D007093:Imidazoles / Q000494:pharmacology; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D009000:Monocytes / Q000276:immunology*; D011493:Protein Kinase C / Q000096:biosynthesis*; D064546:Protein Kinase C beta; D051571:Protein Kinase C-alpha; D011725:Pyridines / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D004791:Enzyme Inhibitors; D005419:Flavonoids; D007093:Imidazoles; D015850:Interleukin-6; D011725:Pyridines; C496628:PRKCA protein, human; D011493:Protein Kinase C; D064546:Protein Kinase C beta; D051571:Protein Kinase C-alpha; D048051:p38 Mitogen-Activated Protein Kinases; C090942:4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)imidazole; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one