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 language | English (US) |
|---|---|
| Pages (from-to) | 85-91 |
| Number of pages | 7 |
| Journal | Diabetes |
| Volume | 54 |
| Issue number | 1 |
| DOIs | |
| State | Published - Jan 2005 |
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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 journal › Article
}
TY - JOUR
T1 - Hyperglycemia induces monocytic release of interleukin-6 via induction of protein kinase C-α and -β
AU - Devaraj, Sridevi
AU - Venugopal, Senthil K.
AU - Singh, Uma
AU - Jialal, Ishwarlal
PY - 2005/1
Y1 - 2005/1
N2 - 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.
AB - 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.
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U2 - 10.2337/diabetes.54.1.85
DO - 10.2337/diabetes.54.1.85
M3 - Article
VL - 54
SP - 85
EP - 91
JO - Diabetes
JF - Diabetes
SN - 0012-1797
IS - 1
ER -