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.
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Authors | A Mortellaro, S Songia, P Gnocchi, M Ferrari, C Fornasiero, R D'Alessio, A Isetta, F Colotta, J Golay |
Journal | Journal of immunology (Baltimore, Md. : 1950)
(J Immunol)
Vol. 162
Issue 12
Pg. 7102-9
(Jun 15 1999)
ISSN: 0022-1767 [Print] United States |
PMID | 10358154
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- DNA-Binding Proteins
- I-kappa B Proteins
- Immunosuppressive Agents
- Interleukin-2
- NF-kappa B
- Transcription Factor AP-1
- Prodigiosin
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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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