15-Deoxy-Δ^12,14,-prostaglandin J₂ inhibits IFN-inducible protein 10/CXC chemokine ligand 10 expression in human microglia: Mechanisms and implications

Regulation of cytokine and chemokine expression in microglia may have implications for CNS inflammatory disorders. In this study we examined the role of the cyclopentenone PG 15-deoxy-Δ^12,14-PGJ₂ (15d-PGJ₂) in microglial inflammatory activation in primary cultures of human fetal microglia. 15d-PGJ₂ potently inhibited the expression of microglial cytokines (IL-1, TNF-α, and IL-6). We found that 15d-PGJ₂ had differential effects on the expression of two α-chemokines; whereas the Glu-Lys-Arg (ELR)-chemokine IFN-inducible protein-10/CXCL10 was inhibited, the ELR⁺ chemokine IL-8/CXCL8 was not inhibited. These findings were shown in primary human microglia and the human monocytic cells line THP-1 cells, using diverse cell stimuli such as bacterial endotoxin, proinflammatory cytokines (IL-1 and TNF-α), IFN-β, and HIV-1. Furthermore, IL-8/CXCL8 expression was induced by 15d-PGJ₂ alone or in combination with TNF-α or HIV-1. Combined results from EMSA, Western blot analysis, and immunocytochemistry showed that 15d-PGJ₂ inhibited NF-κB, Stat1, and p38 MAPK activation in microglia. Adenoviral transduction of super-repressor IκBα, dominant negative MKK6, and dominant negative Ras demonstrated that NF-κB and p38 MAPK were involved in LPS-induced IFN-inducible protein 10/CXCL10 production. Interestingly, although LPS-induced IL-8/CXCL8 was dependent on NF-κB, the baseline or 15d-PGJ₂-mediated IL-8/CXCL8 production was NF-κB independent. Our results demonstrate that 15d-PGJ₂ has opposing effects on the expression of two α-chemokines. These data may have implications for CNS inflammatory diseases.