15d-PGJ2 and rosilglitazone suppress Janus kinase-STAT inflammatory signaling through induction of suppressor of cytokine signaling 1 (SOCS1) and SOCS3 in glia

Peroxisome proliferator-activated receptor (PPAR)-gamma agonists are now emerging as therapeutic drugs for various inflammatory diseases. However, their molecular mechanism of action remains to be elucidated. Here we report a novel mechanism that underlies the PPAR-gamma agonist-mediated suppression of brain inflammation. We show that 15-deoxy-Delta12,14-prostaglandin J(2) (15d-PGJ,) and rosiglitazone reduce the phosphorylation of STAT1 and STAT3 as well as Janus kinase 1 (JAK1) and JAK2 in activated astrocytes and microglia. The PPAR-gamma agonist-mediated reduction in phosphorylation leads to the suppression of JAK-STAT-dependent inflammatory responses. The effects of 15d-PGJ2 and rosiglitazone are not mediated by activation of PPAR-gamma. 15d-PGJ2 and rosiglitazone rapidly induce the transcription of suppressor of cytokine signaling (SOCS) 1 and 3, which in turn inhibit JAK activity in activated glial cells. In addition, Src homology, 2, domain-containing protein phosphatase 2 (SHP2), another negative regulator of JAK activity, is also involved in their anti-inflammatory action. Our data suggest that 15d-PGJ, and rosiglitazone suppress the initiation of JAK-STAT inflammatory signaling independently of PPAR-gamma, thus attenuating brain inflammation.