New immunosuppressive drug PNU156804 blocks IL-2-dependent proliferation and NF-kappa B and AP-1 activation.
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.
Mortellaro
A
A
Department of Immunology and Cell Biology, Istituto Ricerche Farmacologiche Mario Negri, Milan, Italy.
Songia
S
S
Gnocchi
P
P
Ferrari
M
M
Fornasiero
C
C
D'Alessio
R
R
Isetta
A
A
Colotta
F
F
Golay
J
J
D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D016193:G1 Phase / Q000187:drug effects / Q000276:immunology; D006801:Humans; D020672:I-kappa B Proteins; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007376:Interleukin-2 / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000187:drug effects*; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011353:Prodigiosin / Q000031:analogs & derivatives* / Q000494:pharmacology; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000037:antagonists & inhibitors* / Q000378:metabolism
D004268:DNA-Binding Proteins; D020672:I-kappa B Proteins; D007166:Immunosuppressive Agents; D007376:Interleukin-2; D016328:NF-kappa B; D018808:Transcription Factor AP-1; D011353:Prodigiosin