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Effect of 4-trifluoromethyl derivatives of salicylate on nuclear factor kappaB-dependent transcription in human astrocytoma cells.

ABSTRACT: 1. The effect of two derivatives of salicylate, 2-hydroxy-4-trifluoromethylbenzoic acid (HTB) and 2-acetoxy-4-trifluoromethylbenzoic acid (triflusal), on the expression of several proteins displaying pro-inflammatory activities the regulation of which is associated to the transcription factor NF-kappaB, was assayed in the human astrocytoma cell line 1321N1. 2. Tumour necrosis factor-alpha (TNF-alpha) activated NF-kappaB as judged from both the appearance of kappaB-binding activity in the nuclear extracts, the degradation of IkappaB proteins in the cell lysates, and the activation of IkappaB kinases using an immunocomplex kinase assay with glutathione S-transferase (GST)-IkappaB proteins as substrates. 3. HTB up to 3 mM did not inhibit the nuclear translocation of NK-kappaB/Rel proteins as judged from electrophoretic mobility-shift assays; however, HTB inhibited the degradation of IkappaBbeta without significantly affecting the degradation of both IkappaBalpha and IkappaBepsilon. 4. In keeping with their inhibitory effect on IkappaBbeta degradation in the cell lysates, both HTB and triflusal inhibited the phosphorylation of GST-IkappaBbeta elicited by TNF-alpha, without affecting the phosphorylation of GST-IkappaBalpha. 5. The effect of both HTB and triflusal on kappaB-dependent trans-activation was studied by assaying the expression of both cyclo-oxygenase-2 (COX-2) and vascular cell adhesion molecule-1 (VCAM-1). HTB and triflusal inhibited in a dose-dependent manner the expression of COX-2 and VCAM-1 mRNA and the induction of COX-2 protein at therapeutically relevant concentrations. 6. These findings show the complexity of the biochemical mechanisms underlying the activation of NF-kappaB in the different cell types and extend the anti-inflammatory effects of HTB and triflusal to neural cells.

SUBMITTER: Hernandez M

PROVIDER: S-EPMC1572571 | biostudies-literature | 2001 Jan

REPOSITORIES: biostudies-literature

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Effect of 4-trifluoromethyl derivatives of salicylate on nuclear factor kappaB-dependent transcription in human astrocytoma cells.

Hernández M M de Arriba A F AF Merlos M M Fuentes L L Crespo M S MS Nieto M L ML

British journal of pharmacology 20010101 2

1. The effect of two derivatives of salicylate, 2-hydroxy-4-trifluoromethylbenzoic acid (HTB) and 2-acetoxy-4-trifluoromethylbenzoic acid (triflusal), on the expression of several proteins displaying pro-inflammatory activities the regulation of which is associated to the transcription factor NF-kappaB, was assayed in the human astrocytoma cell line 1321N1. 2. Tumour necrosis factor-alpha (TNF-alpha) activated NF-kappaB as judged from both the appearance of kappaB-binding activity in the nuclear ...[more]

PMID: 11159705

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Project description:Activation of transforming growth factor-beta (TGF-beta) and activin receptors leads to phosphorylation of Sma- and Mad-related protein 2 (Smad2) and Smad3, which function as transcription factors to regulate gene expression. Smad7 is a regulatory protein which is able to inhibit TGF-beta and activin signalling in a negative-feedback loop, mediated by a direct regulation by Smad3 and Smad4 via a Smad-binding element (SBE) in the Smad7 promoter. Interestingly, we found that the Smad7 promoter was also regulated by nuclear factor kappaB (NF-kappaB), a transcription factor which plays an important role in inflammation and the immune response. Expression of NF-kappaB p65 subunit was able to inhibit the Smad7 promoter activity, and this inhibition could be reversed by co-expression of IkappaB, an inhibitor of NF-kappaB. In addition, the inhibitory activity of p65 was observed in a minimal promoter that contained only the Smad7 SBE and a TATA box, without any consensus NF-kappaB binding site. This inhibitory effect appeared to be common to other TGF-beta- and activin-responsive promoters, since p65 also inhibited the forkhead-activin-signal-transducer-2-mediated activation of a Xenopus Mix.2 promoter, as well as the Smad3-mediated activation of 3TP-lux which contains PMA-responsive elements and a plasminogen-activator-inhibitor-1 promoter. Activation of endogenous NF-kappaB by tumour necrosis factor-alpha (TNF-alpha) was also able to inhibit the Smad7 promoter in human embryonic kidney 293 cells. In human hepatoma HepG2 cells, TNF-alpha was able to inhibit TGF-beta- and activin-mediated transcriptional activation. Furthermore, overexpression of the transcription co-activator p300 could abrogate the inhibitory effect of NF-kappaB on the Smad7 promoter. Taken together, these data have indicated a novel mode of crosstalk between the Smad and the NF-kappaB signalling cascades at the transcriptional level by competing for a limiting pool of transcription co-activators.

Dataset Information

Effect of 4-trifluoromethyl derivatives of salicylate on nuclear factor kappaB-dependent transcription in human astrocytoma cells.

Publications

Effect of 4-trifluoromethyl derivatives of salicylate on nuclear factor kappaB-dependent transcription in human astrocytoma cells.

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