Lysophosphatidylcholine induces cyclooxygenase-2-dependent IL-6 expression in human cardiac fibroblasts

Cell Mol Life Sci. 2018 Dec;75(24):4599-4617. doi: 10.1007/s00018-018-2916-7. Epub 2018 Sep 18.

Abstract

Lysophosphatidylcholine (LysoPC) has been shown to induce the expression of inflammatory proteins, including cyclooxygenase-2 (COX-2) and interleukin-6 (IL-6), associated with cardiac fibrosis. Here, we demonstrated that LysoPC-induced COX-2 and IL-6 expression was inhibited by silencing NADPH oxidase 1, 2, 4, 5; p65; and FoxO1 in human cardiac fibroblasts (HCFs). LysoPC-induced IL-6 expression was attenuated by a COX-2 inhibitor. LysoPC-induced responses were mediated via the NADPH oxidase-derived reactive oxygen species-dependent JNK1/2 phosphorylation pathway, leading to NF-κB and FoxO1 activation. In addition, we demonstrated that both FoxO1 and p65 regulated COX-2 promoter activity stimulated by LysoPC. Overexpression of wild-type FoxO1 and S256D FoxO1 enhanced COX-2 promoter activity and protein expression in HCFs. These results were confirmed by ex vivo studies, where LysoPC-induced COX-2 and IL-6 expression was attenuated by the inhibitors of NADPH oxidase, NF-κB, and FoxO1. Our findings demonstrate that LysoPC-induced COX-2 expression is mediated via NADPH oxidase-derived reactive oxygen species generation linked to the JNK1/2-dependent pathway leading to FoxO1 and NF-κB activation in HCFs. LysoPC-induced COX-2-dependent IL-6 expression provided novel insights into the therapeutic targets of the cardiac fibrotic responses.

Keywords: COX-2; FoxO1; IL-6; Lysophosphatidylcholine; NF-κB; NOX; ROS.

MeSH terms

  • Animals
  • Cell Line
  • Cyclooxygenase 2 / genetics
  • Cyclooxygenase 2 / immunology*
  • Fibroblasts / immunology*
  • Humans
  • Interleukin-6 / genetics
  • Interleukin-6 / immunology*
  • Lysophosphatidylcholines / immunology*
  • Male
  • Mice, Inbred ICR
  • Myocardium / cytology
  • Myocardium / immunology*
  • NADPH Oxidases / immunology
  • Promoter Regions, Genetic
  • Reactive Oxygen Species / immunology
  • Up-Regulation*

Substances

  • Interleukin-6
  • Lysophosphatidylcholines
  • Reactive Oxygen Species
  • Cyclooxygenase 2
  • NADPH Oxidases