Article: article from journal or magazin.
Cyclopentenone prostaglandin 15-deoxy-Delta(12,14)-prostaglandin J(2) acts as a general inhibitor of inflammatory responses in activated BV-2 microglial cells.
15-deoxy-Delta(12,14)-PGJ(2), a cyclopentenone derivative of PGD(2), was recently reported [Petrova et al., Proc. Natl. Acad. Sci. USA 96 (1999) 4668-4673] to suppress inducible nitric oxide synthase (iNOS) production in microglia and mixed glial cultures stimulated with lipopolysaccharide (LPS). We report here that in addition to suppressing iNOS production, 15d-PGJ(2) also decreases the production of tumor necrosis factor alpha (TNFalpha), interleukin-1 beta (IL-1beta) and cyclooxygenase-2 (COX-2) in LPS-stimulated BV-2 microglial cells, thereby acting as a general inhibitor of microglial activation. Concomitantly, 15d-PGJ(2) itself up-regulates the production of the antioxidant enzyme heme oxygenase-1 (HO-1) and increases intracellular total glutathione levels. To test if increased HO-1 levels were involved in the ability of 15d-PGJ(2) to block microglial activation, we used a HO-1 inhibitor that could block the activity of HO-1. The presence of the HO-1 inhibitor did not alter the 15d-PGJ(2)-induced inhibition of LPS-stimulated iNOS and TNFalpha protein levels, and led to only a partial reduction in the protection offered by 15d-PGJ(2) against LPS-induced nitrite production. These results suggest that HO-1 upregulation by 15d-PGJ(2) is not the primary pathway responsible for the anti-inflammatory action of 15d-PGJ(2) in microglial cells.
Animals, Cell Line, Cyclooxygenase 2, Glutathione/metabolism, Heme Oxygenase (Decyclizing)/antagonists & inhibitors, Heme Oxygenase (Decyclizing)/biosynthesis, Heme Oxygenase-1, Interleukin-1/biosynthesis, Interleukin-1/metabolism, Isoenzymes/biosynthesis, Isoenzymes/metabolism, Lipopolysaccharides, Membrane Proteins, Metalloporphyrins/pharmacology, Mice, Microglia/cytology, Microglia/drug effects, Neuritis/enzymology, Neuritis/immunology, Nitric Oxide Synthase/antagonists & inhibitors, Nitric Oxide Synthase/biosynthesis, Nitric Oxide Synthase Type II, Oxidative Stress/drug effects, Oxidative Stress/immunology, Prostaglandin D2/analogs & derivatives, Prostaglandin D2/pharmacology, Prostaglandin-Endoperoxide Synthases/biosynthesis, Prostaglandin-Endoperoxide Synthases/metabolism, Tumor Necrosis Factor-alpha/antagonists & inhibitors, Tumor Necrosis Factor-alpha/biosynthesis
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