MAP kinase cascades are activated in astrocytes and preadipocytes by 15-deoxy-Delta(12-14)-prostaglandin J(2) and the thiazolidinedione ciglitazone through peroxisome proliferator activator receptor gamma-independent mechanisms involving reactive oxygenated species.
15-Deoxy-Delta(12-14)-prostaglandin J(2) (dPGJ2) and thiazolidinediones are known as ligands for the peroxisome proliferator activator receptor gamma (PPAR gamma) 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 microm). A scavenger of reactive oxygenated species (ROS), N-acetylcysteine (NAC) at 20 mm, 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 PPAR gamma. Ciglitazone (20 microm), 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 PPAR gamma, rosiglitazone, does not activate MAP kinases, indicating that the effect of ciglitazone on MAP kinases is independent of PPAR gamma. 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 PPAR gamma-independent mechanisms involving ROS.
Lennon
Anne Marie
AM
Unité de Recherche Stéroides et Système Nerveux, Unité 488 de l'Institut National de la Santé et de la Recherche Médicale (INSERM), 80 avenue du Général Leclerc, 94276 Le Kremlin-Bicêtre, France.
Ramaugé
Martine
M
Dessouroux
Audrey
A
Pierre
Michel
M
D017667:Adipocytes / Q000187:drug effects* / Q000201:enzymology; D000818:Animals; D001253:Astrocytes / Q000187:drug effects* / Q000201:enzymology; D002478:Cells, Cultured; D004789:Enzyme Activation; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D015230:Prostaglandin D2 / Q000031:analogs & derivatives* / Q000494:pharmacology*; D051381:Rats; D017382:Reactive Oxygen Species; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D013844:Thiazoles / Q000494:pharmacology*; D045162:Thiazolidinediones; D014157:Transcription Factors / Q000378:metabolism*
C097240:15-deoxy-delta(12,14)-prostaglandin J2; D017382:Reactive Oxygen Species; D018160:Receptors, Cytoplasmic and Nuclear; D013844:Thiazoles; D045162:Thiazolidinediones; D014157:Transcription Factors; D015230:Prostaglandin D2; C039671:ciglitazone