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.
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.
Department of Medicine, Research Center of Heart, Brain, Hormone, and Healthy Aging, University of Hong Kong, Hong Kong.
Xiaoyan
X
Hui
Huiying
H
Li
Zhiguang
Z
Zhou
Karen S L
KS
Lam
Yang
Y
Xiao
Donghai
D
Wu
Ke
K
Ding
Yu
Y
Wang
Paul M
PM
Vanhoutte
Aimin
A
Xu
D017667:Adipocytes / Q000378:metabolism; D000818:Animals; D001483:Base Sequence; D015153:Blotting, Western; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation; D016207:Cytokines / Q000378:metabolism; D050556:Fatty Acid-Binding Proteins / Q000502:physiology*; D025461:Feedback, Physiological; D007249:Inflammation / Q000276:immunology / Q000378:metabolism*; D048031:JNK Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008156:Luciferases / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D008969:Molecular Sequence Data; D010766:Phosphorylation; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012689:Sequence Homology, Nucleic Acid; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000378:metabolism*
D016207:Cytokines; D050556:Fatty Acid-Binding Proteins; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D018808:Transcription Factor AP-1; D008156:Luciferases; D048031:JNK Mitogen-Activated Protein Kinases