Differential regulation of chemokine gene expression by 15-deoxy-delta 12,14 prostaglandin J2.
Ligands for peroxisome proliferator-activated receptor gamma (PPARgamma), such as 15-deoxy-Delta(12,14)PGJ2 (15d-PGJ2) have been proposed as a new class of antiinflammatory compounds with possible clinical applications. As there is some controversy over the inhibitory effects of 15d-PGJ2 on chemokine gene expression, we investigated whether 15d-PGJ2 itself affected chemokine gene expression in human monocytes/macrophages and two monocytic cell lines. Here we demonstrate that the 15d-PGJ2 can induce IL-8 gene expression. In contrast, monocyte chemoattractant protein-1 gene expression was suppressed by 15d-PGJ2, while the expression of RANTES was unaltered. Furthermore, concomitant treatment of monocytes/macrophages with 15d-PGJ2 (2.5 x 10(-6) M) potentiated LPS-induced gene expression of IL-8 mRNA, but suppressed PMA-induction of IL-8 mRNA. In addition, treatment of U937 and THP-1 cells with 15d-PGJ2 also resulted in induction of IL-8 gene expression. Further studies demonstrated that 15d-PGJ2 regulated IL-8 gene expression via a ligand-specific and PPARgamma-dependent pathway. Our observations revealed a previous unappreciated function and mechanism of 15d-PGJ2-mediated regulation of cytokine gene expression in monocytes/macrophages.
Zhang
X
X
Laboratory of Experimental Immunology, and Laboratory of Molecular Immunoregulation, Division of Basic Science, National Cancer Institute-Frederick Cancer Research Development Center, National Institute of Health, Frederick, MD 21702, USA.
Wang
J M
JM
Gong
W H
WH
Mukaida
N
N
Young
H A
HA
D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D051836:COUP Transcription Factors; D002474:Cell-Free System / Q000502:physiology; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000096:biosynthesis; D018946:Chemokine CCL5 / Q000096:biosynthesis; D018925:Chemokines / Q000096:biosynthesis* / Q000235:genetics*; D002634:Chemotaxis, Leukocyte / Q000276:immunology; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D016209:Interleukin-8 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D008024:Ligands; D008070:Lipopolysaccharides / Q000494:pharmacology; D009000:Monocytes / Q000276:immunology / Q000378:metabolism; D009504:Neutrophils / Q000276:immunology; D020675:Peroxisomes / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000187:drug effects / Q000276:immunology; D015230:Prostaglandin D2 / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology*; D018160:Receptors, Cytoplasmic and Nuclear / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D011987:Receptors, Steroid; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D014162:Transfection
C097240:15-deoxy-delta(12,14)-prostaglandin J2; D000894:Anti-Inflammatory Agents, Non-Steroidal; D051836:COUP Transcription Factors; D018932:Chemokine CCL2; D018946:Chemokine CCL5; D018925:Chemokines; D004268:DNA-Binding Proteins; D016209:Interleukin-8; D008024:Ligands; D008070:Lipopolysaccharides; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D014157:Transcription Factors; D013755:Tetradecanoylphorbol Acetate; D015230:Prostaglandin D2