The 15-lipoxygenase-modified high density lipoproteins 3 fail to inhibit the TNF-α-induced inflammatory response in human endothelial cells

Angela Pirillo, Patrizia Uboldi, Chiara Bolego, Hartmut Kuhn, Alberico Luigi Catapano

Research output: Contribution to journalArticlepeer-review

Abstract

Endothelial dysfunction represents one of the earliest events in vascular atherogenesis. Proinflammatory stimuli activate endothelial cells, resulting in an increased expression of adhesion molecules and chemoattractants that mediate leukocyte and monocyte adhesion, migration, and homing. High density lipoproteins (HDL) inhibit endothelial cell expression of adhesion molecules in response to proinflammatory stimuli. In the present work, we demonstrate that the modification of HDL3 (the major and the most antiatherogenic HDL subfraction) by 15-lipoxygenase (15-LO), an enzyme overexpressed in the atherosclerotic lesions, impairs the anti-inflammatory activity of this lipoprotein. The 15-LO-modified HDL3 failed to inhibit TNF-α-mediated mRNA and protein induction of adhesion molecules and MCP-1 in several models of human endothelial cells, and promoted inflammatory response by up-regulating the expression of such mediators of inflammation and by increasing monocyte adhesion to endothelial cells. Moreover, 15-LO-modified HDL3 were unable to contrast the formation of reactive oxygen species in cells incubated with TNF-α, and increased the reactive oxygen species content in unstimulated cells. Activation of NF-κB and AP-1 was mainly involved in the expression of adhesion molecules and MCP-1 induced by 15-LO-HDL3. Altogether, these results demonstrate that enzymatic modification induced by 15-LO impaired the protective role of HDL3, generating a dysfunctional lipoprotein endowed with proinflammatory characteristics.

Original languageEnglish
Pages (from-to)2821-2830
Number of pages10
JournalJournal of Immunology
Volume181
Issue number4
Publication statusPublished - Aug 15 2008

ASJC Scopus subject areas

  • Immunology
  • Medicine(all)

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