The cyclopentone prostaglandin 15-deoxy-Delta(12,14) prostaglandin J2 represses nitric oxide, TNF-alpha, and IL-12 production by microglial cells

Prostaglandins are generally considered pro-inflammatory molecules that con tribute to the pathology associated with a variety of immune-mediated disea ses including multiple sclerosis. However, recently it has been demonstrate d that specific cyclopentone prostaglandin metabolites including 15-deoxy-D elta (12,14) prostaglandin J2 (15d-PGJ2) are capable of repressing the prod uction of pro-inflammmatory molecules by cells of the monocyte/macrophage l ineage. Activated microglia produce nitric oxide (NO) and TNF-cr, molecules which can be toxic to cells including oligodendrocytes, thus potentially c ontributing to the pathology associated with multiple sclerosis. The curren t study demonstrates that 15d-PGJ2 inhibits lipopolysachharide (LPS) induct ion of NO and TNF-alpha production by rat primary microglia and mouse N9 mi croglial cells. 15d-PGJ2 also inhibits NO production by microglial cells ac tivated in response to IFN-gamma and TNF-alpha, cytokines believed to be im portant modulators of multiple sclerosis. IL-12 plays a critical role in st imulating the production of Th1 cells, which are believed to contribute to the pathology associated with multiple sclerosis. The current studies demon strate that 15d-PGJ2 represses the production of IL-12 by microglial cells. Collectively, these studies demonstrate that the prostaglandin metabolite 15d-PGJ2 represses microglial production of potentially cytotoxic molecules , as well as molecules capable of altering T-cell phenotype. These in vitro studies suggest the possibility that the prostaglandin 15d-PGJ2 may modula te inflammatory diseases including multiple sclerosis. (C) 2001 Elsevier Sc ience B.V. All rights reserved.