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J Biol Chem ; 285(10): 6960-9, 2010 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-20054003

RESUMO

Interleukin-12 (IL-12), p80, and IL-23 are structurally related cytokines sharing a p40 subunit. We have recently demonstrated that celecoxib and its COX-2-independent analogue 4-trifluoromethyl-celecoxib (TFM-C) inhibit secretion but not transcription of IL-12 (p35/p40) and p80 (p40/p40). This is associated with a mechanism involving altered cytokine-chaperone interaction in the endoplasmic reticulum (ER). In the present study, we found that celecoxib and TFM-C also block secretion of IL-23 (p40/p19 heterodimers). Given the putative ER-centric mode of these compounds, we performed a comprehensive RT-PCR analysis of 23 ER-resident chaperones/foldases and associated co-factors. This revealed that TFM-C induced 1.5-3-fold transcriptional up-regulation of calreticulin, GRP78, GRP94, GRP170, ERp72, ERp57, ERdj4, and ERp29. However, more significantly, a 7-fold up-regulation of homocysteine-inducible ER protein (HERP) was observed. HERP is part of a high molecular mass protein complex involved in ER-associated protein degradation (ERAD). Using co-immunoprecipitation assays, we show that TFM-C induces protein interaction of p80 and IL-23 with HERP. Both HERP siRNA knockdown and HERP overexpression coupled to cycloheximide chase assays revealed that HERP is necessary for degradation of intracellularly retained p80 by TFM-C. Thus, our data suggest that targeting cytokine folding in the ER by small molecule drugs could be therapeutically exploited to alleviate inappropriate inflammation in autoimmune conditions.


Assuntos
Inibidores de Ciclo-Oxigenase 2 , Retículo Endoplasmático/metabolismo , Proteínas de Choque Térmico/metabolismo , Interleucina-12/metabolismo , Interleucina-23/metabolismo , Proteínas de Membrana/metabolismo , Pirazóis , Sulfonamidas , Animais , Celecoxib , Linhagem Celular , Cicloeximida/metabolismo , Inibidores de Ciclo-Oxigenase 2/química , Inibidores de Ciclo-Oxigenase 2/metabolismo , Ecdisterona/análogos & derivados , Ecdisterona/metabolismo , Chaperona BiP do Retículo Endoplasmático , Regulação da Expressão Gênica , Proteínas de Choque Térmico/genética , Humanos , Proteínas de Membrana/genética , Chaperonas Moleculares/genética , Chaperonas Moleculares/metabolismo , Subunidades Proteicas/genética , Subunidades Proteicas/metabolismo , Inibidores da Síntese de Proteínas/metabolismo , Pirazóis/química , Pirazóis/metabolismo , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Sulfonamidas/química , Sulfonamidas/metabolismo
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