Upregulation of MIP‐2 (CXCL2) expression by 15‐deoxy‐Δ 12,14 ‐prostaglandin J 2 in mouse peritoneal macrophages

A peroxisome proliferator‐activated receptor γ (PPAR γ ) ligand, 15‐deoxy‐Δ 12,14 ‐prostaglandin J 2 (15d‐PGJ 2 ), has been reported to possess anti‐inflammatory activity in activated monocytes/macrophages. In this study, we investigated the effect of 15d‐PGJ 2 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 γ ligands, 15d‐PGJ 2 and prostaglandin A1 (PGA1), on the expression of RANTES (regulated upon activation, normal T expressed and secreted; CCL5), MIP‐1 β (CCL4), MIP‐1 α (CCL3), IFN‐ γ ‐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 γ ligands troglitazone and ciglitazone. However, 15d‐PGJ 2 enhanced the expression of LPS‐induced MIP‐2 (CXCL2) mRNA. A specific PPAR γ antagonist (GW9662) had no effect on the inhibitory action of 15d‐PGJ 2 and PGA1 in LPS‐induced chemokine mRNA expression and on the synergistic action of 15d‐PGJ 2 in LPS‐induced MIP‐2 (CXCL2) expression. Moreover, LPS itself reduced the expression of PPAR γ . Although the synergistic effect of 15d‐PGJ 2 on LPS‐induced MIP‐2 (CXCL2) mRNA expression was remarkable, the production of MIP‐2 (CXCL2) in cells treated with 15d‐PGJ 2 and LPS did not increase compared to the production in cells treated with LPS alone. The synergistic action of 15d‐PGJ 2 on LPS‐induced MIP‐2 (CXCL2) mRNA expression was dependent on the activation of nuclear factor‐ κ B (NF‐ κ B), and 15d‐PGJ 2 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‐PGJ 2 on LPS‐induced MIP‐2 (CXCL2) expression is PPAR γ ‐independent, and is mediated by the p38 and SAPK/JNK pathway in mitogen‐activated protein kinase signaling pathways, which activates NF‐ κ B. Our data may give more insights into the different mechanisms contrary to the anti‐inflammatory effect of 15d‐PGJ 2 on the expression of chemokine genes.