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.
Publication types
-
Comparative Study
-
Research Support, Non-U.S. Gov't
-
Research Support, U.S. Gov't, P.H.S.
MeSH terms
-
Administration, Oral
-
Animals
-
Cell Line / drug effects
-
Cells, Cultured / drug effects
-
Cells, Cultured / enzymology
-
Cyclosporine / pharmacology
-
Cyclosporine / therapeutic use*
-
DNA-Binding Proteins / metabolism
-
Dose-Response Relationship, Drug
-
Drug Interactions
-
Drug Synergism
-
Enzyme Inhibitors / pharmacology
-
Enzyme Inhibitors / therapeutic use*
-
Graft Survival / drug effects*
-
Heart Transplantation
-
Humans
-
Immunosuppressive Agents / pharmacology
-
Immunosuppressive Agents / therapeutic use*
-
Interleukins / pharmacology
-
Janus Kinase 2
-
Janus Kinase 3
-
Jurkat Cells / drug effects
-
Jurkat Cells / enzymology
-
Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / metabolism
-
MAP Kinase Signaling System / drug effects
-
Milk Proteins*
-
Phosphorylation / drug effects
-
Prodigiosin / analogs & derivatives*
-
Prodigiosin / pharmacology
-
Prodigiosin / therapeutic use*
-
Protein Processing, Post-Translational / drug effects*
-
Protein-Tyrosine Kinases / antagonists & inhibitors*
-
Proto-Oncogene Proteins*
-
Pyrroles / pharmacology
-
Pyrroles / therapeutic use*
-
Rats
-
Rats, Inbred BUF
-
Rats, Inbred WF
-
STAT5 Transcription Factor
-
Sirolimus / pharmacology
-
Sirolimus / therapeutic use*
-
T-Lymphocytes / drug effects*
-
T-Lymphocytes / enzymology
-
Trans-Activators / metabolism
Substances
-
4-benzyloxy-5-((5-undecyl-2H-pyrrol-2-ylidene)methyl)-2,2'-bi-1H-pyrrole
-
DNA-Binding Proteins
-
Enzyme Inhibitors
-
Immunosuppressive Agents
-
Interleukins
-
Jak3 protein, rat
-
Milk Proteins
-
Proto-Oncogene Proteins
-
Pyrroles
-
STAT5 Transcription Factor
-
STAT5B protein, human
-
Stat5b protein, rat
-
Trans-Activators
-
Cyclosporine
-
Protein-Tyrosine Kinases
-
JAK2 protein, human
-
JAK3 protein, human
-
Jak2 protein, rat
-
Janus Kinase 2
-
Janus Kinase 3
-
Lymphocyte Specific Protein Tyrosine Kinase p56(lck)
-
Prodigiosin
-
Sirolimus