Contribution of cyclopentenone prostaglandins to the resolution of inflammation through the potentiation of apoptosis in activated macrophage

Activation of the macrophage cell line RAW 264.7 with LPS and IFN-gamma ind uces apoptosis through the synthesis of high concentrations of NO due to th e expression of NO synthase-2, In addition to NO, activated macrophages rel ease other molecules involved in the inflammatory response, such as reactiv e oxygen intermediates and PGs, Treatment of macrophages with cyclopentenon e PGs, which are synthesized late in the inflammatory onset, exerted a nega tive regulation on cell activation by impairing the expression of genes inv olved in host defense, among them NO synthase-2, However, despite the atten uation of NO synthesis, the percentage of apoptotic cells increased with re spect to activated cells in the absence of cyclopentenone PGs, Analysis of the mechanisms by which these PGs enhanced apoptosis suggested a potentiati on of superoxide anion synthesis that reacted with NO, leading to the forma tion of higher concentrations of peroxynitrite, a more reactive and proapop totic molecule than the precursors. The effect of the cyclopentenone 15-deo xy-Delta (12,14)-PGJ(2) on superoxide synthesis was dependent on p38 mitoge n-activated protein kinase activity, but was independent of the interaction with peroxisomal proliferator-activated receptor gamma. The potentiation o f apoptosis induced by cyclopentenone PGs involved an increase in the relea se of cytochrome c from the mitochondria to the cytosol and in the nitratio n of this protein. These results suggest a role for cyclopentenone PGs in t he resolution of inflammation by inducing apoptosis of activated cells.