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.
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
P D
PD
Drew
J A
JA
Chavis
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