Upregulation of lipopolysaccharide-induced interleukin-10 by prostaglandin A1 in mouse peritoneal macrophages.
The cyclopentenone prostaglandins (cyPGs) prostaglandin A1 (PGA1) and 15-deoxy-12,14-prostaglandin J2 (15d-PGJ2) have been reported to exhibit antiinflammatory activity in activated monocytes/macrophages. However, the effects of these two cyPGs on the expression of cytokine genes may differ. In this study, we investigated the mechanism of action of PGA1 in lipopolysaccharide (LPS)-induced expression of interleukin (IL)-10 mRNA in mouse peritoneal macrophages. 15d-PGJ2 inhibited expression of LPSinduced IL-10, whereas PGA1 increased LPS-induced IL-10 expression. This synergistic effect of PGA1 on LPS-induced IL-10 expression reached a maximum as early as 2 h after simultaneous PGA1 and LPS treatment (PGA1/LPS), and did not require new protein synthesis. The synergistic effect of PGA1 was inhibited by GW9662, a specific peroxisome proliferator-activated receptor (PPAR) antagonist, and Bay-11-7082, a NF-kappaB inhibitor. The extracellular signalregulated kinases (ERK) inhibitor PD98059 increased the expression of PGA1/LPS-induced IL-10 mRNA, rather than inhibiting the IL-10 expression. Moreover, PGA1 inhibited LPS-induced ERK phosphorylation. The synergistic effect of PGA1 on LPS-induced IL-10 mRNA and protein production was inhibited by p38 inhibitor PD169316, and PGA1 increased LPS-induced p38 phosphorylation. In the case of stress-activated protein kinase/c-Jun NH2-terminal kinase (SAPK/JNK), the SAPK/JNK inhibitor SP600125 did not inhibit IL-10 mRNA synthesis but inhibited the production of IL-10 protein remarkably. These results suggest that the synergistic effect of PGA1 on LPS-induced IL-10 expression is NF-kappaB-dependent and mediated by mitogen-activated protein (MAP) kinases, p38, and SAPK/ JNK signaling pathways, and also associated with the PPARgamma pathway. Our data may provide more insight into the diverse mechanisms of PGA1 effects on the expression of cytokine genes.
Kim
Hyo Young
HY
Department of Microbiology College of Medicine, Yeungnam University, Daegu, Korea.
Kim
Jae Ryong
JR
Kim
Hee Sun
HS
D000818:Animals; D002478:Cells, Cultured; D005786:Gene Expression Regulation; D016753:Interleukin-10 / Q000096:biosynthesis*; D008070:Lipopolysaccharides / Q000494:pharmacology*; D020935:MAP Kinase Signaling System; D017737:Macrophages, Peritoneal / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D047495:PPAR gamma / Q000378:metabolism; D015230:Prostaglandin D2 / Q000031:analogs & derivatives / Q000494:pharmacology; D011454:Prostaglandins A / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015854:Up-Regulation
C097240:15-deoxy-delta(12,14)-prostaglandin J2; D008070:Lipopolysaccharides; D016328:NF-kappa B; D047495:PPAR gamma; D011454:Prostaglandins A; D012333:RNA, Messenger; D016753:Interleukin-10; D020928:Mitogen-Activated Protein Kinases; D015230:Prostaglandin D2; C100573:prostaglandin A1