Activation of PPARalpha or gamma reduces secretion of matrix metalloproteinase 9 but not interleukin 8 from human monocytic THP-1 cells.
Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors that directly control numerous genes of lipid metabolism by binding to response elements in the promoter. It has recently been proposed that PPARgamma may also regulate genes for proinflammatory proteins, not through PPRE binding but by interaction with transcription factors AP-1, STAT, and NF-kappaB. Recent studies with cultured human monocytes, however, have failed to observe an inhibitory effect of PPARgamma agonists on induced expression of TNFalpha and IL-6, genes known to be controlled by AP-1, STAT, and NF-kappaB. In a similar fashion, we show here that PPARalpha (fenofibrate) or PPARgamma (rosiglitazone) agonists failed to modulate LPS-induced secretion of IL-8 in THP-1 cells. When we made parallel observations on another gene, matrix metalloproteinase 9 (MMP-9), we were surprised to find profound downregulation of LPS-induced secretion by both PPARalpha or PPARgamma agonists. These findings suggest that PPAR may regulate only a subset of the proinflammatory genes controlled by AP-1, STAT, and NF-kappaB. Effects of PPARs on MMP-9 may account for the beneficial effect of PPAR agonists in animal models of atherosclerosis.
Shu
H
H
Department of Lipid Biochemistry, Merck Research Laboratories, Rahway, New Jersey, 07065, USA.
Wong
B
B
Zhou
G
G
Li
Y
Y
Berger
J
J
Woods
J W
JW
Wright
S D
SD
Cai
T Q
TQ
D002467:Cell Nucleus / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D011345:Fenofibrate / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D016209:Interleukin-8 / Q000235:genetics*; D007700:Kinetics; D008070:Lipopolysaccharides / Q000494:pharmacology; D020780:Matrix Metalloproteinase 9 / Q000235:genetics*; D009000:Monocytes; D011401:Promoter Regions, Genetic; D018160:Receptors, Cytoplasmic and Nuclear / Q000187:drug effects / Q000502:physiology*; D000077154:Rosiglitazone; D013844:Thiazoles / Q000494:pharmacology*; D045162:Thiazolidinediones; D014157:Transcription Factors / Q000187:drug effects / Q000502:physiology*; D014407:Tumor Cells, Cultured
D004268:DNA-Binding Proteins; D016209:Interleukin-8; D008070:Lipopolysaccharides; D018160:Receptors, Cytoplasmic and Nuclear; D013844:Thiazoles; D045162:Thiazolidinediones; D014157:Transcription Factors; D000077154:Rosiglitazone; D020780:Matrix Metalloproteinase 9; D011345:Fenofibrate