Servizio Comunitario di Informazione in materia di Ricerca e Sviluppo - CORDIS

Antiproliferative mechanism underlying retinoid action in B cells

RA isomers induce a strong growth inhibitory effect on Epstein-Barr virus (EBV)-immortalized lymphoblastoid B cell lines (LCLs), a model of EBV+ lymphoproliferations of immuno-suppressed patients.

This effect is mainly mediated by RARa and occurs through the up-regulation of the CDK inhibitor p27kip-1. RA down-regulates the expression of the p45Skp2 and Cks1 proteins, two essential components of the SCFSkp2 ubiquitin ligase complex that target p27Kip1 for degradation, resulting in a decreased ubiquitination and proteasome-dependent degradation of p27Kip1.

The analysis of the effects of RA on IL-6-induced signalling in LCLs showed that RA induced a down-regulation of IL-6R a-chain (gp80) whereas the expression of the ß-chain (gp130) was unaffected. RA induced a down-regulation of sgp80 (IL-6 agonist) and a slight increase in the levels of sgp130 (IL-6 antagonist).

Analysis of post-receptor events demonstrated that IL-6 stimulation of LCLs triggers JAK1 (but not TYK2) phosphorylation, which results in increased STAT3 phosphorylation and activation.

The finding that RA severely impairs IL-6-dependent signalling in LCLs and inhibits their growth despite the presence of constitutively active JAK/STAT and MAPK cascades provide additional support for a role of RA in the prevention and treatment of EBV-related lymphoproliferative disorders of immuno-suppressed patients.

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Riccardo DOLCETTI, (Head)
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