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New Immunosuppressive Drug PNU156804 Blocks IL-2-Dependent Proliferation and NF-B and AP-1 Activation¹

Alessandra Mortellaro^*, Simona Songia^*, Paola Gnocchi, Mario Ferrari, Chiara Fornasiero, Roberto D’Alessio, Anna Isetta, Francesco Colotta and Josée Golay^2,*

^* Department of Immunology and Cell Biology, Istituto Ricerche Farmacologiche Mario Negri, Milan, Italy; and Department of Pharmacology, Pharmacia and Upjohn Research Center, Nerviano, Italy

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 - and -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-B and AP-1 transcription factors. PNU156804 inhibition of NF-B activation is due to the inhibition of the degradation of IB- and IB-ß. PNU156804 action is restricted to some signaling pathways; it does not affect NF-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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