Selective inhibitor of Janus tyrosine kinase 3, PNU156804, prolongs allograft survival and acts synergistically with cyclosporine but additively with rapamycin.
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.
Stepkowski
Stanislaw M
SM
Department of Surgery/Division of Immunology and Organ Transplantation and University of Texas Medical School at Houston, USA.
Erwin-Cohen
Rebecca A
RA
Behbod
Fariba
F
Wang
Mou-Er
ME
Qu
Xienui
X
Tejpal
Neelam
N
Nagy
Zsuzsanna S
ZS
Kahan
Barry D
BD
Kirken
Robert A
RA
D000284:Administration, Oral; D000818:Animals; D002460:Cell Line / Q000187:drug effects; D002478:Cells, Cultured / Q000187:drug effects / Q000201:enzymology; D016572:Cyclosporine / Q000494:pharmacology / Q000627:therapeutic use*; D004268:DNA-Binding Proteins / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D006085:Graft Survival / Q000187:drug effects*; D016027:Heart Transplantation; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology / Q000627:therapeutic use*; D007378:Interleukins / Q000494:pharmacology; D053614:Janus Kinase 2; D053616:Janus Kinase 3; D019169:Jurkat Cells / Q000187:drug effects / Q000201:enzymology; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008894:Milk Proteins; D010766:Phosphorylation / Q000187:drug effects; D011353:Prodigiosin / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use*; D011499:Protein Processing, Post-Translational / Q000187:drug effects*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011518:Proto-Oncogene Proteins; D011758:Pyrroles / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D011915:Rats, Inbred BUF; D011920:Rats, Inbred WF; D050799:STAT5 Transcription Factor; D020123:Sirolimus / Q000494:pharmacology / Q000627:therapeutic use*; D013601:T-Lymphocytes / Q000187:drug effects* / Q000201:enzymology; D015534:Trans-Activators / Q000378:metabolism
C119625:4-benzyloxy-5-((5-undecyl-2H-pyrrol-2-ylidene)methyl)-2,2'-bi-1H-pyrrole; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D007166:Immunosuppressive Agents; D007378:Interleukins; C507936:Jak3 protein, rat; D008894:Milk Proteins; D011518:Proto-Oncogene Proteins; D011758:Pyrroles; D050799:STAT5 Transcription Factor; C494095:STAT5B protein, human; C494097:Stat5b protein, rat; D015534:Trans-Activators; D016572:Cyclosporine; D011505:Protein-Tyrosine Kinases; C507924:JAK2 protein, human; C507933:JAK3 protein, human; C507927:Jak2 protein, rat; D053614:Janus Kinase 2; D053616:Janus Kinase 3; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D011353:Prodigiosin; D020123:Sirolimus