¹Department of Microbiology and Aging-associated Vascular Disease Research Center, College of Medicine, Yeungnam University, Daegu, Korea

Correspondence: Dr HS Kim, Department of Microbiology, College of Medicine, Yeungnam University, 317-1 Daemyungdong Namgu, Daegu 705-717, Korea. E-mail: heesun@med.yu.ac.kr

Received 22 May 2006; Accepted 3 July 2006; Published online 28 November 2006.

Abstract

A peroxisome proliferator-activated receptor (PPAR) ligand, 15-deoxy-^12,14-prostaglandin J₂ (15d-PGJ₂), has been reported to possess anti-inflammatory activity in activated monocytes/macrophages. In this study, we investigated the effect of 15d-PGJ₂ on the lipopolysaccharide (LPS)-induced expression of chemokine mRNAs, especially macrophage inhibitory protein (MIP)-2 (CXCL2), in mouse peritoneal macrophages. The inhibitory actions of the natural PPAR ligands, 15d-PGJ₂ and prostaglandin A1 (PGA1), on the expression of RANTES (regulated upon activation, normal T expressed and secreted; CCL5), MIP-1 (CCL4), MIP-1 (CCL3), IFN--inducible protein 10 kilodaltons (IP-10; CXCL10) and monocyte chemoattractant protein-1 (MCP-1; CCL2) mRNA in LPS-treated cells were stronger than those of the synthetic PPAR ligands troglitazone and ciglitazone. However, 15d-PGJ₂ enhanced the expression of LPS-induced MIP-2 (CXCL2) mRNA. A specific PPAR antagonist (GW9662) had no effect on the inhibitory action of 15d-PGJ₂ and PGA1 in LPS-induced chemokine mRNA expression and on the synergistic action of 15d-PGJ₂ in LPS-induced MIP-2 (CXCL2) expression. Moreover, LPS itself reduced the expression of PPAR. Although the synergistic effect of 15d-PGJ₂ on LPS-induced MIP-2 (CXCL2) mRNA expression was remarkable, the production of MIP-2 (CXCL2) in cells treated with 15d-PGJ₂ and LPS did not increase compared to the production in cells treated with LPS alone. The synergistic action of 15d-PGJ₂ on LPS-induced MIP-2 (CXCL2) mRNA expression was dependent on the activation of nuclear factor-B (NF-B), and 15d-PGJ₂ increased the phosphorylation of p38 and stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK) in cells stimulated with LPS. These results suggest that the synergistic effect of 15d-PGJ₂ on LPS-induced MIP-2 (CXCL2) expression is PPAR-independent, and is mediated by the p38 and SAPK/JNK pathway in mitogen-activated protein kinase signaling pathways, which activates NF-B. Our data may give more insights into the different mechanisms contrary to the anti-inflammatory effect of 15d-PGJ₂ on the expression of chemokine genes.