Inflammatory intracellular pathways activated by electronegative LDL in monocytes

Montserrat Estruch, Jose Luis Sanchez-Quesada, Jordi Ordoñez-Llanos, Sonia Benitez

Research output: Contribution to journalArticleResearchpeer-review

8 Citations (Scopus)

Abstract

© 2016 Elsevier B.V. All rights reserved. Aims Electronegative LDL (LDL(-)) is a plasma LDL subfraction that induces cytokine release in monocytes through toll-like receptor 4 (TLR4) activation. However, the intracellular pathways induced by LDL(-) downstream TLR4 activation are unknown. We aimed to identify the pathways activated by LDL(-) leading to cytokine release in monocytes. Methods and results We determined LDL(-)-induced activation of several intracellular kinases in protein extracts from monocytes using a multikinase ELISA array. LDL(-) induced higher p38 mitogen-activated protein kinase (MAPK) phosphorylation than native LDL. This was corroborated by a specific cell-based assay and it was dependent on TLR4 and phosphoinositide 3-kinase (PI3k)/Akt pathway. P38 MAPK activation was involved in cytokine release promoted by LDL(-). A specific ELISA showed that LDL(-) activated cAMP response-element binding (CREB) in a p38 MAPK dependent manner. P38 MAPK was also involved in the nuclear factor kappa-B (NF-kB) and activating protein-1 (AP-1) activation by LDL(-). We found that NF-kB, AP-1 and CREB inhibitors decreased LDL(-)-induced cytokine release, mainly on MCP1, IL6 and IL10 release, respectively. Conclusions LDL(-) promotes p38 MAPK phosphorylation through TLR4 and PI3k/Akt pathways. Phosphorylation of p38 MAPK is involved in NF-kB, AP-1 and CREB activation, leading to LDL(-)-induced cytokine release in monocytes.
Original languageEnglish
Pages (from-to)963-969
JournalBiochimica et Biophysica Acta - Molecular and Cell Biology of Lipids
Volume1861
Issue number9
DOIs
Publication statusPublished - 1 Sep 2016

Keywords

  • Cell signaling
  • Cytokines
  • Electronegative LDL
  • MAP kinases
  • Toll-like receptor (TLR)
  • Transcription factors

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