title: Ligation of RARgamma inhibits proliferation of phytohaemagglutinin-stimulated T-cells via down-regulating JAK3 protein levels.
abstract: The mechanisms whereby Vitamin A regulates the immune system are poorly understood. We have shown previously that retinoic acids, the Vitamin A derivatives, promote both apoptosis of neglected thymocytes and the activation-induced cell death of peripheral T-cells via ligating the nuclear retinoid receptor (RAR) gamma. In the present study, we found that human peripheral T-cells express RARalpha and gamma, but not RARbeta. Increasing concentrations of 9-cis RA inhibited phytohaemagglutinin (PHA)-induced proliferation of T-cells, an effect that could be mimicked only by addition of RARgamma agonists and could be inhibited by an RARgamma antagonist. Interleukin-2 (IL-2) produced is known to mediate PHA-induced proliferation of T lymphocytes. Ligation of RARgamma did not affect the PHA-induced high affinity IL-2 receptor expression, slightly reduced the PHA-induced IL-2 production, but interfered with the IL-2-mediated signal transduction resulting in inhibition of PHA-induced phosphorylation of retinoblastoma protein and of up-regulation of Bcl-2. Janus kinases JAK1 and JAK3 play a determinant role in IL-2-dependent signal transduction. Ligation of RARgamma did not affect the levels of JAK1, but prevented IL-2-induced expression of JAK3 resulting in inhibition of PHA-induced phosphorylation of Stat5 molecules. Our data suggest that the previously observed toxic effect of high concentrations of retinoids on the immune system might be mediated via formation of 9-cis RA, which via ligation of RARgamma not only induces cell death in immature thymocytes, but inhibits proliferation of T-cells as well.
authors.affiliation: Department of Biochemistry and Molecular Biology, Research Center of Molecular Medicine, University Medical School of Debrecen, Nagyerdei krt.98, H-4012 Debrecen, Hungary.
authors.forename: Katalin
authors.initials: K
authors.lastname: Ludányi
authors.forename: Zsuzsanna S
authors.initials: ZS
authors.lastname: Nagy
authors.forename: Magdolna
authors.initials: M
authors.lastname: Alexa
authors.forename: Uwe
authors.initials: U
authors.lastname: Reichert
authors.forename: Serge
authors.initials: S
authors.lastname: Michel
authors.forename: László
authors.initials: L
authors.lastname: Fésüs
authors.forename: Zsuzsa
authors.initials: Z
authors.lastname: Szondy
mesh_terms: D000077556:Alitretinoin; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000378:metabolism; D015536:Down-Regulation; D006801:Humans; D007376:Interleukin-2 / Q000378:metabolism; D053616:Janus Kinase 3; D008894:Milk Proteins / Q000378:metabolism; D010766:Phosphorylation; D010835:Phytohemagglutinins / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D018168:Receptors, Retinoic Acid / Q000378:metabolism*; D050799:STAT5 Transcription Factor; D015398:Signal Transduction / Q000502:physiology; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism*; D015534:Trans-Activators / Q000378:metabolism; D014212:Tretinoin / Q000494:pharmacology; D000097768:Retinoic Acid Receptor gamma
chemical_list: D000077556:Alitretinoin; D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D007376:Interleukin-2; D053616:Janus Kinase 3; D008894:Milk Proteins; D010835:Phytohemagglutinins; D011505:Protein-Tyrosine Kinases; D018168:Receptors, Retinoic Acid; D050799:STAT5 Transcription Factor; D015534:Trans-Activators; D014212:Tretinoin; D000097768:Retinoic Acid Receptor gamma; C507933:JAK3 protein, human