Selective inhibitor of Janus tyrosine kinase 3, PNU156804, prolongs allograft survival and acts synergistically with cyclosporine but additively with rapamycin.

Department of Surgery/Division of Immunology and Organ Transplantation and University of Texas Medical School at Houston, USA.
Blood (Impact Factor: 10.45). 02/2002; 99(2):680-9.
Source: PubMed

ABSTRACT Janus kinase 3 (Jak3) is a cytoplasmic tyrosine (Tyr) kinase associated with the interleukin-2 (IL-2) receptor common gamma chain (gamma(c)) that is activated by multiple T-cell growth factors (TCGFs) such as IL-2, -4, and -7. Using human T cells, it was found that a recently discovered variant of the undecylprodigiosin family of antibiotics, PNU156804, previously shown to inhibit IL-2-induced cell proliferation, also blocks IL-2-mediated Jak3 auto-tyrosine phosphorylation, activation of Jak3 substrates signal transducers and activators of transcription (Stat) 5a and Stat5b, and extracellular regulated kinase 1 (Erk1) and Erk2 (p44/p42). Although PNU156804 displayed similar efficacy in blocking Jak3-dependent T-cell proliferation by IL-2, -4, -7, or -15, it was more than 2-fold less effective in blocking Jak2-mediated cell growth, its most homologous Jak family member. A 14-day alternate-day oral gavage with 40 to 120 mg/kg PNU156804 extended the survival of heart allografts in a dose-dependent fashion. In vivo, PNU156804 acted synergistically with the signal 1 inhibitor cyclosporine A (CsA) and additively with the signal 3 inhibitor rapamycin to block allograft rejection. It is concluded that inhibition of signal 3 alone by targeting Jak3 in combination with a signal 1 inhibitor provides a unique strategy to achieve potent immunosuppression.

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Available from: Zsuzsanna S Nagy, Sep 27, 2015
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    • "Prodigiosins and related molecules have been previously reported to possess redox properties leading to important biological consequences like DNA cleavage. Besides showing antibiotic property and selective cytotoxicity against melanoma and liver cancer cells [1], these are also potentially useful immunosuppressive agents as activators of JAK-3, a cytoplasmic tyrosine kinase [6]. However, they are primarily valued as potential anti-cancer agents. "
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