15d-PGJ2 and rosiglitazone 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(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.
Park
Eun Jung
EJ
Department of Pharmacology, Ajou University School of Medicine, Suwon, Korea 442-721.
Park
Soo Young
SY
Joe
Eun-hye
EH
Jou
Ilo
I
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D001253:Astrocytes / Q000378:metabolism; D002352:Carrier Proteins / Q000096:biosynthesis / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors*; D005786:Gene Expression Regulation / Q000187:drug effects; D007249:Inflammation / Q000188:drug therapy / Q000378:metabolism / Q000517:prevention & control; D053613:Janus Kinase 1; D053614:Janus Kinase 2; D009457:Neuroglia / Q000187:drug effects* / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D015230:Prostaglandin D2 / Q000031:analogs & derivatives* / Q000494:pharmacology*; D014176:Protein Biosynthesis; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011506:Proteins / Q000502:physiology*; D011518:Proto-Oncogene Proteins; D051381:Rats; D017207:Rats, Sprague-Dawley; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists; D012097:Repressor Proteins; D000077154:Rosiglitazone; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; D015398:Signal Transduction / Q000187:drug effects; D000071222:Suppressor of Cytokine Signaling 1 Protein; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D013844:Thiazoles / Q000494:pharmacology*; D045162:Thiazolidinediones; D015534:Trans-Activators / Q000037:antagonists & inhibitors*; D014157:Transcription Factors / Q000819:agonists
D000893:Anti-Inflammatory Agents; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D011506:Proteins; D011518:Proto-Oncogene Proteins; D018160:Receptors, Cytoplasmic and Nuclear; D012097:Repressor Proteins; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; C491589:Socs1 protein, rat; C491410:Socs3 protein, rat; C494081:Stat1 protein, rat; C494088:Stat3 protein, rat; D000071222:Suppressor of Cytokine Signaling 1 Protein; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D013844:Thiazoles; D045162:Thiazolidinediones; D015534:Trans-Activators; D014157:Transcription Factors; D000077154:Rosiglitazone; C037112:9-deoxy-delta-9-prostaglandin D2; D011505:Protein-Tyrosine Kinases; C507906:Jak1 protein, rat; C507927:Jak2 protein, rat; D053613:Janus Kinase 1; D053614:Janus Kinase 2; D015230:Prostaglandin D2