title: Anti-inflammatory roles of retinoic acid in rat brain astrocytes: Suppression of interferon-gamma-induced JAK/STAT phosphorylation.
abstract: The anti-inflammatory effect of retinoic acid (RA) has been investigated for several decades. However, the underlying mechanisms responsible for this effect are largely unknown. In this study, we demonstrate that 9-cis-RA (cRA) and all-trans-RA (tRA) inhibit interferon-gamma (IFN-gamma)-induced inflammatory responses in astrocytes. In primary cultured rat brain astrocytes and C6 astroglioma cells, both cRA and tRA decreased IFN-gamma-induced expression of interferon regulatory factor-1. Both RA isoforms also reduced IFN-gamma-induced activation of signal transducers and activators of transcription (STAT)1, STAT3, Janus kinase (JAK)1, and JAK2. This inhibitory effect was significant when cells were pre-treated with RA prior to IFN-gamma. Furthermore, the effect of pre-treated RA was abolished in the presence of cycloheximide, indicating a requirement for de novo protein synthesis. Suppressors of cytokine signaling (SOCS), which are negative regulators of the JAK/STAT pathway, may be candidate mediators of the anti-inflammatory function of RA. Both cRA and tRA induced SOCS3 mRNA expression. These results suggest that RA induces an anti-inflammatory effect by suppressing the activation of the JAK/STAT pathway in IFN-gamma-treated astrocytes. SOCS3 may be at least one of the mechanisms that mediate the anti-inflammatory roles of RA.
authors.affiliation: Neuroscience Graduate Program, Ajou University School of Medicine, Suwon 442-721, Republic of Korea.
authors.forename: Woo-Hyuck
authors.initials: WH
authors.lastname: Choi
authors.forename: Kyung-Ae
authors.initials: KA
authors.lastname: Ji
authors.forename: Sae-Bom
authors.initials: SB
authors.lastname: Jeon
authors.forename: Myung-Soon
authors.initials: MS
authors.lastname: Yang
authors.forename: Ho
authors.initials: H
authors.lastname: Kim
authors.forename: Kyoung-Jin
authors.initials: KJ
authors.lastname: Min
authors.forename: Minho
authors.initials: M
authors.lastname: Shong
authors.forename: Ilo
authors.initials: I
authors.lastname: Jou
authors.forename: Eun-Hye
authors.initials: EH
authors.lastname: Joe
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001253:Astrocytes / Q000378:metabolism*; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism; D003513:Cycloheximide / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000378:metabolism; D007249:Inflammation; D007371:Interferon-gamma / Q000378:metabolism*; D053613:Janus Kinase 1; D053614:Janus Kinase 2; D010766:Phosphorylation; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012097:Repressor Proteins / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; D000071222:Suppressor of Cytokine Signaling 1 Protein; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D014212:Tretinoin / Q000378:metabolism* / Q000494:pharmacology*
chemical_list: D000893:Anti-Inflammatory Agents; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D011500:Protein Synthesis Inhibitors; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; 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; D015534:Trans-Activators; D014157:Transcription Factors; D014212:Tretinoin; D007371:Interferon-gamma; D003513:Cycloheximide; D011505:Protein-Tyrosine Kinases; C507906:Jak1 protein, rat; C507927:Jak2 protein, rat; D053613:Janus Kinase 1; D053614:Janus Kinase 2