dc.contributor.author | McLaughlin, M | |
dc.contributor.author | Alloza Moral, Iraide | |
dc.contributor.author | Quoc, H. P. | |
dc.contributor.author | Scott, C. J. | |
dc.contributor.author | Hirabayashi, Y. | |
dc.contributor.author | Vandenbroeck, Koen | |
dc.date.accessioned | 2024-02-08T10:22:05Z | |
dc.date.available | 2024-02-08T10:22:05Z | |
dc.date.issued | 2010-03-05 | |
dc.identifier.citation | Journal of Biological Chemistry 285(10) : 6960-6969 (2010) | es_ES |
dc.identifier.issn | 0021-9258 | |
dc.identifier.uri | http://hdl.handle.net/10810/65267 | |
dc.description.abstract | 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. | es_ES |
dc.description.sponsorship | This work was supported by Grants RRG11.5 RSG/1726 (to K. V.) from the
Northern Ireland R&D Office for Health and Personal Social Services, Iker-
basque, the Basque Foundation for Science, Bilbao, Spain, and the Minis-
terio de Ciencia e Innovacio´ n, Madrid, Spain (MEC-2008; SAF2008-00433). | |
dc.language.iso | eng | es_ES |
dc.publisher | American Society for Biochemistry and Molecular Biology, Inc | es_ES |
dc.relation | info:eu-repo/grantAgreement/MEC/SAF2008-00433 | |
dc.rights | info:eu-repo/semantics/openAccess | es_ES |
dc.rights.uri | http://creativecommons.org/licenses/by/4.0 | |
dc.title | Inhibition of secretion of interleukin (IL)-12/IL-23 family cytokines by 4-trifluoromethyl-celecoxib is coupled to degradation via the endoplasmic reticulum stress protein HERP | es_ES |
dc.type | info:eu-repo/semantics/article | es_ES |
dc.rights.holder | © 2010 ASBMB. Currently published by Elsevier Inc; originally published by American Society for Biochemistry and Molecular Biology, under the terms of the Creative Commons CC-BY license | |
dc.relation.publisherversion | https://www.jbc.org/article/S0021-9258(19)58684-7 | |
dc.identifier.doi | /10.1074/jbc.M109.056614 | |
dc.departamentoes | Fisiología | es_ES |
dc.departamentoeu | Fisiologia | es_ES |