Cyclopentenone prostaglandin 15-deoxy-Δ^12,14-prostaglandin J₂ acts as a general inhibitor of inflammatory responses in activated BV-2 microglial cells

15-deoxy-Δ^12,14-PGJ₂, a cyclopentenone derivative of PGD₂, 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-PGJ₂ also decreases the production of tumor necrosis factor alpha (TNFα), interleukin-1 beta (IL-1β) and cyclooxygenase-2 (COX-2) in LPS-stimulated BV-2 microglial cells, thereby acting as a general inhibitor of microglial activation. Concomitantly, 15d-PGJ₂ 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-PGJ₂ 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-PGJ₂-induced inhibition of LPS-stimulated iNOS and TNFα protein levels, and led to only a partial reduction in the protection offered by 15d-PGJ₂ against LPS-induced nitrite production. These results suggest that HO-1 upregulation by 15d-PGJ₂ is not the primary pathway responsible for the anti-inflammatory action of 15d-PGJ₂ in microglial cells. (C) 2000 Elsevier Science B.V.