Differential effects of lipoprotein lipase on tumor necrosis factor-α and interferon-γ-mediated gene expression in human endothelial cells

Rama S. Kota, Chilakamarti V. Ramana, Fatima A. Tenorio, Richard I. Enelow, John C Rutledge

Research output: Contribution to journalArticlepeer-review

31 Scopus citations

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 languageEnglish (US)
Pages (from-to)31076-31084
Number of pages9
JournalJournal of Biological Chemistry
Volume280
Issue number35
DOIs
StatePublished - Sep 2 2005

ASJC Scopus subject areas

  • Biochemistry

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