Abstract
Previously, IL-1β secretion from Type 2 diabetic patients has been shown to be increased compared with controls. In this study, we aimed to delineate the mechanism of IL-1β induction under high-glucose (HG) conditions in human monocytes. THP-1 cells cultured in normal glucose were treated with increasing concentrations of D-glucose (10-25 mM) for 6-72 h. IL-1β and IL-1 receptor antagonist levels were measured by ELISA and Western blots, whereas mRNA was quantitated by RTPCR. Specific inhibitors and small interfering RNAs of PKC, p38, ERK1/2, NF-κB, and NADPH oxidase were used to determine the mediators in parallel experiments under HG conditions. IL-1β-secreted protein, cellular protein, and mRNA increase under HG conditions is time and dose dependent, with maximum increase at 15 mM (48 h; P < 0.05). IL-1 receptor antagonist release was time and dose dependent, similar to IL-1β expression pattern; however, the molar ratio of IL-1β to IL-1RA was increased. Data from inhibitor and small interfering RNA experiments indicate that IL-1β release under HG is mediated by PKC-α, via phosphorylation of p38 MAPK, and ERK1/2 leading to NF-κB activation, resulting in increased mRNA and protein for IL-1β. At the same time, it appears that NADPH oxidase via p47phox activates NF-κB, resulting in increased IL-1β secretion. Data suggest that, under HG conditions, monocytes release significantly higher amounts of IL-1β through multiple mechanisms, further compounding the disease progression. Targeting signaling pathways mediating IL-1β release could result in the amelioration of inflammation and possibly diabetic vasculopathies.
| Original language | English (US) |
|---|---|
| Journal | American Journal of Physiology - Endocrinology and Metabolism |
| Volume | 293 |
| Issue number | 1 |
| DOIs | |
| State | Published - Jul 2007 |
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Keywords
- Diabetes
- Interleukin-1β
- p38 phosphorylation
- Protein kinase C
ASJC Scopus subject areas
- Physiology
- Endocrinology
- Biochemistry
Cite this
High glucose induces IL-1β expression in human monocytes : Mechanistic insights. / Dasu, Mohan R.; Devaraj, Sridevi; Jialal, Ishwarlal.
In: American Journal of Physiology - Endocrinology and Metabolism, Vol. 293, No. 1, 07.2007.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - High glucose induces IL-1β expression in human monocytes
T2 - Mechanistic insights
AU - Dasu, Mohan R.
AU - Devaraj, Sridevi
AU - Jialal, Ishwarlal
PY - 2007/7
Y1 - 2007/7
N2 - Previously, IL-1β secretion from Type 2 diabetic patients has been shown to be increased compared with controls. In this study, we aimed to delineate the mechanism of IL-1β induction under high-glucose (HG) conditions in human monocytes. THP-1 cells cultured in normal glucose were treated with increasing concentrations of D-glucose (10-25 mM) for 6-72 h. IL-1β and IL-1 receptor antagonist levels were measured by ELISA and Western blots, whereas mRNA was quantitated by RTPCR. Specific inhibitors and small interfering RNAs of PKC, p38, ERK1/2, NF-κB, and NADPH oxidase were used to determine the mediators in parallel experiments under HG conditions. IL-1β-secreted protein, cellular protein, and mRNA increase under HG conditions is time and dose dependent, with maximum increase at 15 mM (48 h; P < 0.05). IL-1 receptor antagonist release was time and dose dependent, similar to IL-1β expression pattern; however, the molar ratio of IL-1β to IL-1RA was increased. Data from inhibitor and small interfering RNA experiments indicate that IL-1β release under HG is mediated by PKC-α, via phosphorylation of p38 MAPK, and ERK1/2 leading to NF-κB activation, resulting in increased mRNA and protein for IL-1β. At the same time, it appears that NADPH oxidase via p47phox activates NF-κB, resulting in increased IL-1β secretion. Data suggest that, under HG conditions, monocytes release significantly higher amounts of IL-1β through multiple mechanisms, further compounding the disease progression. Targeting signaling pathways mediating IL-1β release could result in the amelioration of inflammation and possibly diabetic vasculopathies.
AB - Previously, IL-1β secretion from Type 2 diabetic patients has been shown to be increased compared with controls. In this study, we aimed to delineate the mechanism of IL-1β induction under high-glucose (HG) conditions in human monocytes. THP-1 cells cultured in normal glucose were treated with increasing concentrations of D-glucose (10-25 mM) for 6-72 h. IL-1β and IL-1 receptor antagonist levels were measured by ELISA and Western blots, whereas mRNA was quantitated by RTPCR. Specific inhibitors and small interfering RNAs of PKC, p38, ERK1/2, NF-κB, and NADPH oxidase were used to determine the mediators in parallel experiments under HG conditions. IL-1β-secreted protein, cellular protein, and mRNA increase under HG conditions is time and dose dependent, with maximum increase at 15 mM (48 h; P < 0.05). IL-1 receptor antagonist release was time and dose dependent, similar to IL-1β expression pattern; however, the molar ratio of IL-1β to IL-1RA was increased. Data from inhibitor and small interfering RNA experiments indicate that IL-1β release under HG is mediated by PKC-α, via phosphorylation of p38 MAPK, and ERK1/2 leading to NF-κB activation, resulting in increased mRNA and protein for IL-1β. At the same time, it appears that NADPH oxidase via p47phox activates NF-κB, resulting in increased IL-1β secretion. Data suggest that, under HG conditions, monocytes release significantly higher amounts of IL-1β through multiple mechanisms, further compounding the disease progression. Targeting signaling pathways mediating IL-1β release could result in the amelioration of inflammation and possibly diabetic vasculopathies.
KW - Diabetes
KW - Interleukin-1β
KW - p38 phosphorylation
KW - Protein kinase C
UR - http://www.scopus.com/inward/record.url?scp=34547119919&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=34547119919&partnerID=8YFLogxK
U2 - 10.1152/ajpendo.00718.2006
DO - 10.1152/ajpendo.00718.2006
M3 - Article
C2 - 17426109
AN - SCOPUS:34547119919
VL - 293
JO - American Journal of Physiology - Renal Fluid and Electrolyte Physiology
JF - American Journal of Physiology - Renal Fluid and Electrolyte Physiology
SN - 1931-857X
IS - 1
ER -