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15-Deoxy-^12,14-Prostaglandin J₂ Inhibits IFN-Inducible Protein 10/CXC Chemokine Ligand 10 Expression in Human Microglia: Mechanisms and Implications¹

Department of Pathology, Albert Einstein College of Medicine, Bronx, NY 10461

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-^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-, and IL-6). We found that 15d-PGJ₂ had differential effects on the expression of two -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-), IFN-, and HIV-1. Furthermore, IL-8/CXCL8 expression was induced by 15d-PGJ₂ alone or in combination with TNF- or HIV-1. Combined results from EMSA, Western blot analysis, and immunocytochemistry showed that 15d-PGJ₂ inhibited NF-B, Stat1, and p38 MAPK activation in microglia. Adenoviral transduction of super-repressor IB, dominant negative MKK6, and dominant negative Ras demonstrated that NF-B 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-B, the baseline or 15d-PGJ₂-mediated IL-8/CXCL8 production was NF-B independent. Our results demonstrate that 15d-PGJ₂ has opposing effects on the expression of two -chemokines. These data may have implications for CNS inflammatory diseases.

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