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.
Koppal
T
T
Department of Cell and Molecular Biology, Northwestern University Medical School, Ward 4-202, 303 E. Chicago Avenue, Chicago, IL 60611, USA.
Petrova
T V
TV
Van Eldik
L J
LJ
D000818:Animals; D002460:Cell Line; D051546:Cyclooxygenase 2; D005978:Glutathione / Q000378:metabolism; D006419:Heme Oxygenase (Decyclizing) / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism; D051547:Heme Oxygenase-1; D007375:Interleukin-1 / Q000096:biosynthesis / Q000378:metabolism; D007527:Isoenzymes / Q000096:biosynthesis / Q000378:metabolism; D008070:Lipopolysaccharides; D008565:Membrane Proteins; D008665:Metalloporphyrins / Q000494:pharmacology; D051379:Mice; D017628:Microglia / Q000166:cytology / Q000187:drug effects / Q000201:enzymology / Q000276:immunology; D009443:Neuritis / Q000201:enzymology / Q000276:immunology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D018384:Oxidative Stress / Q000187:drug effects / Q000276:immunology; D015230:Prostaglandin D2 / Q000031:analogs & derivatives* / Q000494:pharmacology; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism
C097240:15-deoxy-delta(12,14)-prostaglandin J2; D007375:Interleukin-1; D007527:Isoenzymes; D008070:Lipopolysaccharides; D008565:Membrane Proteins; D008665:Metalloporphyrins; D014409:Tumor Necrosis Factor-alpha; C055421:tin mesoporphyrin; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D005978:Glutathione; D015230:Prostaglandin D2