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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Anti-Inflammatory Agents / pharmacology
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Astrocytes / metabolism
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Carrier Proteins / biosynthesis
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Carrier Proteins / physiology*
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DNA-Binding Proteins / antagonists & inhibitors*
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Gene Expression Regulation / drug effects
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Inflammation / drug therapy
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Inflammation / metabolism
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Inflammation / prevention & control
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Janus Kinase 1
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Janus Kinase 2
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Neuroglia / drug effects*
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Neuroglia / metabolism
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Phosphorylation / drug effects
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Prostaglandin D2 / analogs & derivatives*
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Prostaglandin D2 / pharmacology*
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Protein Biosynthesis
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Protein-Tyrosine Kinases / antagonists & inhibitors*
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Proteins / physiology*
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Proto-Oncogene Proteins*
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Rats
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Rats, Sprague-Dawley
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Receptors, Cytoplasmic and Nuclear / agonists
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Repressor Proteins*
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Rosiglitazone
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STAT1 Transcription Factor
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STAT3 Transcription Factor
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Signal Transduction / drug effects
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Suppressor of Cytokine Signaling 1 Protein
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Suppressor of Cytokine Signaling 3 Protein
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Suppressor of Cytokine Signaling Proteins
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Thiazoles / pharmacology*
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Thiazolidinediones*
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Trans-Activators / antagonists & inhibitors*
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Transcription Factors / agonists
Substances
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Anti-Inflammatory Agents
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Carrier Proteins
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DNA-Binding Proteins
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Proteins
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Proto-Oncogene Proteins
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Receptors, Cytoplasmic and Nuclear
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Repressor Proteins
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STAT1 Transcription Factor
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STAT3 Transcription Factor
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Socs1 protein, rat
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Socs3 protein, rat
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Stat1 protein, rat
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Stat3 protein, rat
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Suppressor of Cytokine Signaling 1 Protein
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Suppressor of Cytokine Signaling 3 Protein
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Suppressor of Cytokine Signaling Proteins
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Thiazoles
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Thiazolidinediones
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Trans-Activators
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Transcription Factors
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Rosiglitazone
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9-deoxy-delta-9-prostaglandin D2
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Protein-Tyrosine Kinases
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Jak1 protein, rat
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Jak2 protein, rat
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Janus Kinase 1
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Janus Kinase 2
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Prostaglandin D2