All-trans retinoic acid suppresses interleukin-6 expression in interleukin-1-stimulated synovial fibroblasts by inhibition of ERK1/2 pathway independently of RAR activation.
Arthritis Res Ther
; 10(6): R141, 2008.
Article
em En
| MEDLINE
| ID: mdl-19068145
ABSTRACT
INTRODUCTION:
Interleukin-6 (IL-6) is thought to play a pathogenic role in rheumatoid arthritis and synovium is a major source of IL-6 release. We investigated the ability of retinoids to suppress IL-6 expression in IL-1-stimulated synovial fibroblasts, with special care to the contribution of retinoic acid receptor (RAR) and retinoid X receptor (RXR) subtypes, and the implication of the mitogen-activated protein kinase (MAPK) pathway.METHODS:
RAR-alpha, -beta, and -gamma and RXR-alpha, -beta, and -gamma levels were determined by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) or Western blot in rat synovial fibroblasts stimulated with 10 ng/mL of IL-1beta. Stimulated levels of IL-6 were assessed by RT-qPCR or immunoassays in the presence or absence of 1 microM all-trans retinoic acid (ATRA) (RAR agonist) or 0.3 microM BMS-649 (RXR agonist). The contribution of RAR subtypes was checked with selective agonists or small interfering RNAs. The effect of ATRA on upstream MAPK (p38 MAPK, c-Jun N-terminal kinase [JNK], and extracellularly regulated kinase 1/2 [ERK1/2]) was assessed by Western blot, and the contribution of the ERK1/2 pathway to the activation of pro-inflammatory transcription factors was studied by TransAm assays.RESULTS:
Synovial fibroblasts expressed all RAR and RXR subtypes except RXR-gamma. In IL-1-stimulated cells, ATRA, but not BMS-649, reduced IL-6 expression whereas selective RAR agonists were inactive. The inhibitory effect of ATRA on IL-6 was not affected by the silencing of RAR subtypes. ATRA also reduced the phosphorylation of ERK1/2, but not of p38 MAPK or of JNK. The suppressive effect of ATRA on the activation of activator protein-1 (AP-1) and nuclear factor-IL-6 (NF-IL-6) was reproduced by the MEK1 (mitogen-activated protein extracellularly regulated kinase kinase 1) inhibitor PD-98059, whereas ATRA and PD-98059 had no effect on NF-kappaB activation.CONCLUSIONS:
Among RAR and RXR agonists, only ATRA inhibited IL-1-induced IL-6 expression in rat synovial fibroblasts by inhibiting ERK1/2 pathway and subsequent activation of AP-1 and NF-IL-6 independently of RAR.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Membrana Sinovial
/
Tretinoína
/
Interleucina-6
/
Interleucina-1
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Receptores do Ácido Retinoico
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Proteína Quinase 1 Ativada por Mitógeno
/
Proteína Quinase 3 Ativada por Mitógeno
Limite:
Animals
Idioma:
En
Ano de publicação:
2008
Tipo de documento:
Article