Upregulation of interleukin-8 expression by prostaglandin D2 metabolite 15-deoxy-delta12, 14 prostaglandin J2 (15d-PGJ2) in human THP-1 macrophages

Atherosclerosis. 2002 Jan;160(1):11-20. doi: 10.1016/s0021-9150(01)00541-x.

Abstract

Interleukin-8 (IL-8) is one of cytokines detected at sites of inflammation and in macrophage-foam cells of atherosclerotic lesions. The expression of IL-8 gene can be induced in cholesterol loaded THP-1 macrophages by oxidized low density lipoprotein. We report for the first time that the expression of human IL-8 gene in THP-1 macrophages is upregulated in a time- and concentration-dependent manner by prostaglandin D2 metabolite 15-deoxy-delta12, 14 prostaglandin J2 (15d-PGJ2), which is a natural ligand for activation of peroxisome proliferator-activated receptor-gamma transcription factor. Studies to identify the signal transduction pathways involved showed that IL-8 upregulation-mediated by 15d-PGJ2 was markedly inhibited when the THP-1 macrophages were incubated with a highly selective and cell-permeable inhibitor of the mitogen-activated protein kinase (MAPK) signaling pathway, 2'-amino-3'-methoxyflavone (PD98059). This inhibition was concentration-dependent, suggesting that 15d-PGJ2 regulates the expression of IL-8 gene in THP-1 macrophages through a MAPK signaling pathway. In contrast, THP-1 macrophages when treated with pyrrolidine dithiocarbamate, an anti-oxidant and the selective inhibitor for nuclear factor kappaB, showed an enhanced 15d-PGJ2-mediated upregulation of IL-8 gene expression. The data presented in this report may contribute to unravel some of the mechanisms behind the inflammatory component of atherosclerosis.

Publication types

  • Comparative Study
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Cholesterol, LDL / drug effects
  • Cholesterol, LDL / genetics
  • Cholesterol, LDL / metabolism
  • Dose-Response Relationship, Drug
  • Humans
  • Immunologic Factors / pharmacology*
  • Interleukin-8 / biosynthesis*
  • Interleukin-8 / genetics*
  • Macrophages / metabolism*
  • Mitogen-Activated Protein Kinases / antagonists & inhibitors
  • Mitogen-Activated Protein Kinases / pharmacology
  • Muscle, Smooth, Vascular / cytology
  • Muscle, Smooth, Vascular / metabolism
  • NF-kappa B / biosynthesis
  • NF-kappa B / drug effects
  • NF-kappa B / genetics
  • Prostaglandin D2 / analogs & derivatives*
  • Prostaglandin D2 / metabolism*
  • Prostaglandin D2 / pharmacology*
  • RNA, Messenger / drug effects
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Receptors, Cytoplasmic and Nuclear / biosynthesis
  • Receptors, Cytoplasmic and Nuclear / drug effects
  • Receptors, Cytoplasmic and Nuclear / genetics
  • Signal Transduction / drug effects
  • Signal Transduction / genetics
  • Transcription Factors / biosynthesis
  • Transcription Factors / drug effects
  • Transcription Factors / genetics
  • Tretinoin / pharmacology
  • Tumor Cells, Cultured
  • Up-Regulation / drug effects
  • Up-Regulation / genetics*

Substances

  • 15-deoxy-delta(12,14)-prostaglandin J2
  • Cholesterol, LDL
  • Immunologic Factors
  • Interleukin-8
  • NF-kappa B
  • RNA, Messenger
  • Receptors, Cytoplasmic and Nuclear
  • Transcription Factors
  • Tretinoin
  • Mitogen-Activated Protein Kinases
  • Prostaglandin D2