BACKGROUND AND PURPOSE: Preliminary results in human mesangial cells (MC) suggested that all-trans retinoic acid (ATRA) increased the expression of COX-2 and the production of prostaglandin E2 (PGE2), a PG with anti-inflammatory effects in MC. The aim of this work is to confirm that ATRA increases the expression of COX-2 in MC and to examine the mechanisms involved. EXPERIMENTAL APPROACH: Cultured MC were treated with ATRA. COX expression and kinase activity were analyzed by Western blot. Transcriptional mechanisms were analyzed by Northern blot, RT-PCR and promoter assays. KEY RESULTS: COX-2 and COX-1 expression and PGE2 production were increased by ATRA. COX-2 played a role in PGE2 production as production was only partially inhibited by COX-1 inhibitor SC-560. COX-2 up-regulation by ATRA was due to transcriptional mechanisms as pre-incubation with actinomycin D abolished it and ATRA increased the expression of COX-2 mRNA and the activity of a human COX-2 promoter construct, whereas post-transcriptional mechanisms were not found. Retinoic acid receptors (RAR) were not involved in the up-regulation of COX-2 by ATRA since it was not inhibited by RAR-pan-antagonists and the RAR-pan-agonist TTNPB did not up-regulate COX-2. Instead ATRA might act through a sustained activation of extracellular signal-regulated kinase 1/2 (ERK1/2) since up-regulation of COX-2 was prevented by inhibition of the activation of ERK1/2 with PD098059. Also ERK1/2, as well as downstream signalling proteins from ERK1/2, remained phosphorylated when COX-2 increased 24 h later. CONCLUSIONS AND IMPLICATIONS: These results highlight the relevance of RAR-independent mechanisms to the biological effects of ATRA. Published online 7 August 2006.
BACKGROUND AND PURPOSE: Preliminary results in human mesangial cells (MC) suggested that all-trans retinoic acid (ATRA) increased the expression of COX-2 and the production of prostaglandin E2 (PGE2), a PG with anti-inflammatory effects in MC. The aim of this work is to confirm that ATRA increases the expression of COX-2 in MC and to examine the mechanisms involved. EXPERIMENTAL APPROACH: Cultured MC were treated with ATRA. COX expression and kinase activity were analyzed by Western blot. Transcriptional mechanisms were analyzed by Northern blot, RT-PCR and promoter assays. KEY RESULTS:COX-2 and COX-1 expression and PGE2 production were increased by ATRA. COX-2 played a role in PGE2 production as production was only partially inhibited by COX-1 inhibitor SC-560. COX-2 up-regulation by ATRA was due to transcriptional mechanisms as pre-incubation with actinomycin D abolished it and ATRA increased the expression of COX-2 mRNA and the activity of a humanCOX-2 promoter construct, whereas post-transcriptional mechanisms were not found. Retinoic acid receptors (RAR) were not involved in the up-regulation of COX-2 by ATRA since it was not inhibited by RAR-pan-antagonists and the RAR-pan-agonist TTNPB did not up-regulate COX-2. Instead ATRA might act through a sustained activation of extracellular signal-regulated kinase 1/2 (ERK1/2) since up-regulation of COX-2 was prevented by inhibition of the activation of ERK1/2 with PD098059. Also ERK1/2, as well as downstream signalling proteins from ERK1/2, remained phosphorylated when COX-2 increased 24 h later. CONCLUSIONS AND IMPLICATIONS: These results highlight the relevance of RAR-independent mechanisms to the biological effects of ATRA. Published online 7 August 2006.
Authors: Y Alsayed; S Uddin; N Mahmud; F Lekmine; D V Kalvakolanu; S Minucci; G Bokoch; L C Platanias Journal: J Biol Chem Date: 2000-11-01 Impact factor: 5.157
Authors: YuanYuan Bao; Ghionul Ibram; William S Blaner; Charles P Quesenberry; Ling Shen; Ian W McKeague; Catherine A Schaefer; Ezra S Susser; Alan S Brown Journal: Schizophr Res Date: 2012-02-29 Impact factor: 4.939