Abstract
Lipoprotein lipase (LPL) is a key enzyme in the hydrolysis of triglyceride-rich lipoproteine. In vascular diseases, such as atherosclerosis, inflammation plays an important role in the pathogenesis of the disease. We examined the role of LPL in modulating tumor necrosis factor-α (TNF-α)- and interferon-γ (IFN-γ)-mediated inflammatory cytokine signal transduction pathways in human aortic endothelial cells (HAECs). LPL significantly suppressed TNF-α-induced gene expression, and this suppression was reversed by tetrahydrolipstatin and heparinase. In contrast, LPL synergistically enhanced IFN-γ-induced gene expression in HAECs. To elucidate the molecular mechanisms of LPL action, we investigated the role of transcription factors nuclear factor kappa B (NF-κB) and signal transducer and activator of transcription factor 1 (Stat1). The anti-inflammatory response of LPL in suppressing TNF-α-induced gene expression was a result of its inhibition of NF-κB activity by the abrogation of IκB-α degradation and phosphorylation of the p65 subunit. Although LPL alone had no effect on Stat1 activation, LPL enhanced IFN-γ-induced phosphorylation of Stat1 on tyrosine 701 and serine 727, as well as Stat1-mediated transactivation. The synergistic effect of LPL on IFN-γ-induced Stat1 activation was mediated by enhanced activation of the tyrosine kinase JAK2 and was abrogated by LY294002, a specific inhibitor of the phosphatidylinositol 3′-kinase pathway. Our studies indicate that LPL has differential effects on several inflammatory pathways known to be important in atherosclerosis.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 31076-31084 |
| Number of pages | 9 |
| Journal | Journal of Biological Chemistry |
| Volume | 280 |
| Issue number | 35 |
| DOIs | |
| State | Published - Sep 2 2005 |
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ASJC Scopus subject areas
- Biochemistry
Cite this
Differential effects of lipoprotein lipase on tumor necrosis factor-α and interferon-γ-mediated gene expression in human endothelial cells. / Kota, Rama S.; Ramana, Chilakamarti V.; Tenorio, Fatima A.; Enelow, Richard I.; Rutledge, John C.
In: Journal of Biological Chemistry, Vol. 280, No. 35, 02.09.2005, p. 31076-31084.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Differential effects of lipoprotein lipase on tumor necrosis factor-α and interferon-γ-mediated gene expression in human endothelial cells
AU - Kota, Rama S.
AU - Ramana, Chilakamarti V.
AU - Tenorio, Fatima A.
AU - Enelow, Richard I.
AU - Rutledge, John C
PY - 2005/9/2
Y1 - 2005/9/2
N2 - Lipoprotein lipase (LPL) is a key enzyme in the hydrolysis of triglyceride-rich lipoproteine. In vascular diseases, such as atherosclerosis, inflammation plays an important role in the pathogenesis of the disease. We examined the role of LPL in modulating tumor necrosis factor-α (TNF-α)- and interferon-γ (IFN-γ)-mediated inflammatory cytokine signal transduction pathways in human aortic endothelial cells (HAECs). LPL significantly suppressed TNF-α-induced gene expression, and this suppression was reversed by tetrahydrolipstatin and heparinase. In contrast, LPL synergistically enhanced IFN-γ-induced gene expression in HAECs. To elucidate the molecular mechanisms of LPL action, we investigated the role of transcription factors nuclear factor kappa B (NF-κB) and signal transducer and activator of transcription factor 1 (Stat1). The anti-inflammatory response of LPL in suppressing TNF-α-induced gene expression was a result of its inhibition of NF-κB activity by the abrogation of IκB-α degradation and phosphorylation of the p65 subunit. Although LPL alone had no effect on Stat1 activation, LPL enhanced IFN-γ-induced phosphorylation of Stat1 on tyrosine 701 and serine 727, as well as Stat1-mediated transactivation. The synergistic effect of LPL on IFN-γ-induced Stat1 activation was mediated by enhanced activation of the tyrosine kinase JAK2 and was abrogated by LY294002, a specific inhibitor of the phosphatidylinositol 3′-kinase pathway. Our studies indicate that LPL has differential effects on several inflammatory pathways known to be important in atherosclerosis.
AB - Lipoprotein lipase (LPL) is a key enzyme in the hydrolysis of triglyceride-rich lipoproteine. In vascular diseases, such as atherosclerosis, inflammation plays an important role in the pathogenesis of the disease. We examined the role of LPL in modulating tumor necrosis factor-α (TNF-α)- and interferon-γ (IFN-γ)-mediated inflammatory cytokine signal transduction pathways in human aortic endothelial cells (HAECs). LPL significantly suppressed TNF-α-induced gene expression, and this suppression was reversed by tetrahydrolipstatin and heparinase. In contrast, LPL synergistically enhanced IFN-γ-induced gene expression in HAECs. To elucidate the molecular mechanisms of LPL action, we investigated the role of transcription factors nuclear factor kappa B (NF-κB) and signal transducer and activator of transcription factor 1 (Stat1). The anti-inflammatory response of LPL in suppressing TNF-α-induced gene expression was a result of its inhibition of NF-κB activity by the abrogation of IκB-α degradation and phosphorylation of the p65 subunit. Although LPL alone had no effect on Stat1 activation, LPL enhanced IFN-γ-induced phosphorylation of Stat1 on tyrosine 701 and serine 727, as well as Stat1-mediated transactivation. The synergistic effect of LPL on IFN-γ-induced Stat1 activation was mediated by enhanced activation of the tyrosine kinase JAK2 and was abrogated by LY294002, a specific inhibitor of the phosphatidylinositol 3′-kinase pathway. Our studies indicate that LPL has differential effects on several inflammatory pathways known to be important in atherosclerosis.
UR - http://www.scopus.com/inward/record.url?scp=24744469233&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=24744469233&partnerID=8YFLogxK
U2 - 10.1074/jbc.M412189200
DO - 10.1074/jbc.M412189200
M3 - Article
VL - 280
SP - 31076
EP - 31084
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
SN - 0021-9258
IS - 35
ER -