Adipocyte fatty acid-binding protein modulates inflammatory responses in macrophages through a positive feedback loop involving c-Jun NH2-terminal kinases and activator protein-1

J Biol Chem. 2010 Apr 2;285(14):10273-80. doi: 10.1074/jbc.M109.097907. Epub 2010 Feb 9.

Abstract

Adipocyte fatty acid-binding protein (A-FABP) has emerged as an important mediator of inflammation in macrophages. Macrophage-selective ablation of A-FABP alone is sufficient to prevent the development of high cholesterol diet-induced atherosclerosis in apoE-deficient mice. However, the precise mechanisms whereby A-FABP modulates inflammation remain elusive. Here, we report that A-FABP forms a finely tuned positive loop between JNK and activator protein-1 (AP-1) to exacerbate lipopolysaccharide (LPS)-induced inflammatory responses in macrophages. Real time PCR and luciferase reporter analysis showed that LPS induced A-FABP expression through transcriptional activation. This effect was mediated by JNK, which promoted the recruitment of c-Jun to a highly conserved AP-1 consensus binding motif located within the proximal region of the A-FABP promoter. LPS-induced transactivation of the A-FABP gene was diminished by either pharmacological inhibition of JNK or knocking down c-Jun or by mutating the AP-1 recognition site within the proximal region (-122 to -116 bp) of the A-FABP promoter. Conversely, the LPS-evoked phosphorylation of JNK, activation of AP-1, and production of pro-inflammatory cytokines were markedly attenuated by pharmacological or genetic suppression of A-FABP in macrophages. Furthermore, the LPS-induced elevation in A-FABP expression could also be prevented by the selective A-FABP inhibitor BMS309403. These findings support the notion that pharmacological inhibition of A-FABP represents a valid strategy for treating inflammation-related disorders such as atherosclerosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipocytes / metabolism
  • Animals
  • Base Sequence
  • Blotting, Western
  • Cells, Cultured
  • Chromatin Immunoprecipitation
  • Cytokines / metabolism
  • Fatty Acid-Binding Proteins / physiology*
  • Feedback, Physiological
  • Inflammation / immunology
  • Inflammation / metabolism*
  • JNK Mitogen-Activated Protein Kinases / genetics
  • JNK Mitogen-Activated Protein Kinases / metabolism*
  • Lipopolysaccharides / pharmacology
  • Luciferases / metabolism
  • Macrophages / metabolism*
  • Mice
  • Molecular Sequence Data
  • Phosphorylation
  • Promoter Regions, Genetic / genetics
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Sequence Homology, Nucleic Acid
  • Transcription Factor AP-1 / genetics
  • Transcription Factor AP-1 / metabolism*

Substances

  • Cytokines
  • Fatty Acid-Binding Proteins
  • Lipopolysaccharides
  • RNA, Messenger
  • Transcription Factor AP-1
  • Luciferases
  • JNK Mitogen-Activated Protein Kinases