MAP Kinase Cascades Are Activated in Astrocytes and Preadipocytes by 15-Deoxy-Δ12–14-prostaglandin J2 and the Thiazolidinedione Ciglitazone through Peroxisome Proliferator Activator Receptor γ-independent Mechanisms Involving Reactive Oxygenated Species

15-Deoxy-Δ 12–14 -prostaglandin J 2 (dPGJ2) and thiazolidinediones are known as ligands for the peroxisome proliferator activator receptor γ (PPARγ) a member of the nuclear receptor superfamily. Herein, we show that dPGJ2 activates, in cultured primary astrocytes, Erk, Jnk, p38 MAP kinase, and ASK1, a MAP kinase kinase kinase, which can be involved in the activation of Jnk and p38 MAP kinase. The activation kinetic is similar for the three MAP kinase. The activation of the MAP kinases is detectable around 0.5 h. The activation increases with dPGJ2 in a dose dependent manner (0–15 μ m ). A scavenger of reactive oxygenated species (ROS), N -acetylcysteine (NAC) at 20 m m , completely suppresses the activation of MAP kinases and ASK1, suggesting a role for oxidative stress in the activation mechanism. Other prostaglandin cyclopentenones than dPGJ2, A 2 , and to a lesser degree, A 1 also stimulate the MAP kinases, although they do not bind to PPARγ. Ciglitazone (20 μ m ), a thiazolidinedione that mimics several effects of dPGJ2 in different cell types, also activates the three MAP kinase families and ASK1 in cultured astrocytes. However the activation is more rapid (it is detectable at 0.25 h) and more sustained (it is still strong after 4 h). NAC prevents the activation of the three MAP kinase families by ciglitazone. Another thiazolidinedione that binds to PPARγ, rosiglitazone, does not activate MAP kinases, indicating that the effect of ciglitazone on MAP kinases is independent of PPAR γ. Ciglitazone and less strongly dPGJ2 activate Erk in undifferentiated cells of the adipocyte cell line 1B8. Ciglitazone also activates Jnk and p38 MAP kinase in these preadipocytes. Our findings suggest that a part of the biological effects of dPGJ2 and ciglitazone involve the activation of the three MAP kinase families probably through PPARγ-independent mechanisms involving ROS.