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New immunosuppressive drug PNU156804 blocks IL-2-dependent proliferation and NF-kappa B and AP-1 activation.

Abstract
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 alpha- and gamma-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-kappa B and AP-1 transcription factors. PNU156804 inhibition of NF-kappa B activation is due to the inhibition of the degradation of I kappa B-alpha and I kappa B-beta. PNU156804 action is restricted to some signaling pathways; it does not affect NF-kappa B 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.
AuthorsA Mortellaro, S Songia, P Gnocchi, M Ferrari, C Fornasiero, R D'Alessio, A Isetta, F Colotta, J Golay
JournalJournal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 162 Issue 12 Pg. 7102-9 (Jun 15 1999) ISSN: 0022-1767 [Print] United States
PMID10358154 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • DNA-Binding Proteins
  • I-kappa B Proteins
  • Immunosuppressive Agents
  • Interleukin-2
  • NF-kappa B
  • Transcription Factor AP-1
  • Prodigiosin
Topics
  • B-Lymphocytes (cytology, immunology, metabolism)
  • Cells, Cultured
  • DNA-Binding Proteins (antagonists & inhibitors, metabolism)
  • G1 Phase (drug effects, immunology)
  • Humans
  • I-kappa B Proteins
  • Immunosuppressive Agents (pharmacology)
  • Interleukin-2 (antagonists & inhibitors, pharmacology)
  • Lymphocyte Activation (drug effects)
  • NF-kappa B (antagonists & inhibitors, metabolism)
  • Prodigiosin (analogs & derivatives, pharmacology)
  • T-Lymphocytes (cytology, immunology, metabolism)
  • Transcription Factor AP-1 (antagonists & inhibitors, metabolism)

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