FKBP proteins as a new target for pholyphenols-mediated NF-kB inhibition

CAMISAY M.F.; DE LEO S.A.; COX M.B.; GALIGNIANA M.D.; ERLEJMAN A.G.

Buenos Aires

Conferencia; 6th International Conferece on Polyphenols and Health; 2013

NF-kB (RelA/p50) activation depends on its nuclear translocation, and certain polyphenols could affect it, by different mechanism. FK506 binding proteins (FKBPs) FKBP51 and FKBP52 regulates the subcellular localization of steroid receptors. We found that RelA interact with FKBP51, whereas phorbol-ester (PMA)-stimulation promoted its exchange with FKBP52. The nuclear translocation rate of RelA was delayed by FKBP51 and favored by FKBP52. Hence we propose a functional study of FKBPs peptidyl-prolyl-cis/trans-isomerase activity (PPIase-activity), and the effects of (-)-epigallocatechin-3-gallate (EGCG), on NF-kB transcriptional response. HEK-293T cells were transfected with FKBPs expression-plasmids, and PMA-stimulated (100ng/ml-6h). NF-kB transcriptional response (100%activation) measured by a gene reporter-assay, was significantly abrogated by FKBP51 (50%activation), whereas FKBP52 showed a positive effect (200%activation). The lack of PPIase-activity in FKBP51 not changed it effect. However, FKBP52F67Y and FKBP52F130Y mutant (both without PPIase-activity) did inhibited NF-kB activation (lower than 50%activation), which was reverted by competition with FKBP52 wild type. EGCG was previously described as PPIase inhibitor. The pre-incubation with EGCG (25uM-1h) blocked the stimulatory effects of FKBP52, while in non-transfected cells in same condition did not affects significantly NF-kB activation. We postulate that FKBP52 is a stimulator factor of NF-kB, whose effect depends on its intrinsic PPIase-activity, and is competed by FKBP51. These observations raise the possibility that NF-kB function may be regulated according to the expression balance of both FKBPs, and build up a new biological target for polyphenols mechanism of actions.