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

Authors
Park, EJ; Park, SY; Joe, EH; Jou, I
Citation
The Journal of biological chemistry, 278(17):14747-14752, 2003
Journal Title
The Journal of biological chemistry
ISSN
0021-92581083-351X
Abstract
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(2)) 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-PGJ(2) and rosiglitazone are not mediated by activation of PPAR-gamma. 15d-PGJ(2) 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(2) and rosiglitazone suppress the initiation of JAK-STAT inflammatory signaling independently of PPAR-gamma, thus attenuating brain inflammation.
MeSH terms
AnimalsAnti-Inflammatory Agents/pharmacologyAstrocytes/metabolismCarrier Proteins/biosynthesisCarrier Proteins/physiology*DNA-Binding Proteins/antagonists & inhibitors*Gene Expression Regulation/drug effectsInflammation/drug therapyInflammation/metabolismInflammation/prevention & controlJanus Kinase 1Janus Kinase 2Neuroglia/drug effects*Neuroglia/metabolismPhosphorylation/drug effectsProstaglandin D2/analogs & derivatives*Prostaglandin D2/pharmacology*Protein BiosynthesisProtein-Tyrosine Kinases/antagonists & inhibitors*Proteins/physiology*Proto-Oncogene Proteins*RatsRats, Sprague-DawleyReceptors, Cytoplasmic and Nuclear/agonistsRepressor Proteins*STAT1 Transcription FactorSTAT3 Transcription FactorSignal Transduction/drug effectsSuppressor of Cytokine Signaling ProteinsThiazoles/pharmacology*Thiazolidinediones*Trans-Activators/antagonists & inhibitors*Transcription Factors/agonists
DOI
10.1074/jbc.M210819200
PMID
12584205
Appears in Collections:
Journal Papers > School of Medicine / Graduate School of Medicine > Pharmacology
Journal Papers > Research Organization > Chronic Inflammatory Disease Research Center
AJOU Authors
박, 은정조, 은혜주, 일로
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