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 contribute to the pathology associated with a variety of immune-mediated diseases including multiple sclerosis. However, recently it has been demonstrated that specific cyclopentone prostaglandin metabolites including 15-deoxy-Delta(12,14) prostaglandin J2 (15d-PGJ2) are capable of repressing the production of pro-inflammatory molecules by cells of the monocyte/macrophage lineage. Activated microglia produce nitric oxide (NO) and TNF-alpha, molecules which can be toxic to cells including oligodendrocytes, thus potentially contributing to the pathology associated with multiple sclerosis. The current study demonstrates that 15d-PGJ2 inhibits lipopolysachharide (LPS) induction of NO and TNF-alpha production by rat primary microglia and mouse N9 microglial cells. 15d-PGJ2 also inhibits NO production by microglial cells activated in response to IFN-gamma and TNF-alpha, cytokines believed to be important modulators of multiple sclerosis. IL-12 plays a critical role in stimulating the production of Th1 cells, which are believed to contribute to the pathology associated with multiple sclerosis. The current studies demonstrate 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 modulate inflammatory diseases including multiple sclerosis.
Drew
P D
PD
Department of Anatomy, University of Arkansas for Medical Sciences, Slot 510, Shorey Building, Room 922, 4301 W. Markham Street, Little Rock, AR 72205, USA. drewpauld@exchange.uams.edu
Chavis
J A
JA
D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D007371:Interferon-gamma / Q000494:pharmacology; D018664:Interleukin-12 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D008070:Lipopolysaccharides / Q000494:pharmacology; D017628:Microglia / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D009569:Nitric Oxide / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D015230:Prostaglandin D2 / Q000031:analogs & derivatives / Q000494:pharmacology*; D051381:Rats; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000494:pharmacology
C097240:15-deoxy-delta(12,14)-prostaglandin J2; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D018799:Intercellular Adhesion Molecule-1; D018664:Interleukin-12; D009569:Nitric Oxide; D007371:Interferon-gamma; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D015230:Prostaglandin D2