| Autor: |
Alessandra Mortellaro, Songia, S., Gnocchi, P., Ferrari, M., Fornasiero, C., D Alessio, R., Isetta, A., Colotta, F., Golay, J. |
| Předmět: |
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| Zdroj: |
Scopus-Elsevier |
| Popis: |
We had previously shown that the drug undecylprodigiosin (UP) blocks human lymphocyte proliferation in vitro. We have now investigated the mechanism of action of a new analogue of UP, PNU156804, which shows a more favorable activity profile than UP in mice. We demonstrate here that the biological effect of PNU156804 in vitro is indistinguishable from UP: PNU156804 blocks human T cell proliferation in mid-late G1, as determined by cell cycle analysis, expression of cyclins, and cyclin-dependent kinases and retinoblastoma phosphorylation. In addition, we show that PNU156804 does not block significantly the induction of either IL-2 or IL-2R α- and γ-chains but inhibits IL-2-dependent T cell proliferation. We have investigated several molecular pathways that are known to be activated by IL-2 in T cells. We show that PNU156804 does not inhibit c-myc and bcl-2 mRNA induction. On the other hand, PNU156804 efficiently inhibits the activation of the NF-κB and AP-1 transcription factors. PNU156804 inhibition of NF-κB activation is due to the inhibition of the degradation of IκB-α and IκB-β. PNU156804 action is restricted to some signaling pathways; it does not affect NF-κB activation by PMA in T cells but blocks that induced by CD40 cross-linking in B lymphocytes. We conclude that the prodigiosin family of immunosuppressants is a new family of molecules that show a novel target specificity clearly distinct from that of other immunosuppressive drugs such as cyclosporin A, FK506, and rapamycin. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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