Novel IL-21 signaling pathway up-regulates c-Myc and induces apoptosis of diffuse large B-cell lymphomas.
Interleukin-21 (IL-21), a member of the IL-2 cytokine family, has diverse regulatory effects on natural killer (NK), T, and B cells. In contrast to other cytokines that are usually immunostimulatory, IL-21 can induce apoptosis of murine B cells at specific activation-differentiation stages. This effect may be used for treatment of B-cell malignancies. Herein we report that diffuse large B-cell lymphoma (DLBCL) cell lines exhibit widespread expression of the IL-21 receptor (IL-21R) and that IL-21 stimulation leads to cell-cycle arrest and caspase-dependent apoptosis. IL-21 also induces apoptosis in de novo DLBCL primary tumors but does not affect viability of human healthy B cells. Furthermore, IL-21 promotes tumor regression and prolongs survival of mice harboring xenograft DLBCL tumors. The antilymphoma effects of this cytokine are dependent on a mechanism involving IL-21-activated signal transducer and activator of transcription 3 (STAT3) up-regulating expression of c-Myc. This up-regulation promotes a decrease in expression of antiapoptotic Bcl-2 and Bcl-X(L) proteins triggering cell death. Our results represent one of the first examples in which the STAT3-c-Myc signaling pathway, which can promote survival and oncogenesis, can induce apoptosis in neoplastic cells. Moreover, based on IL-21's potency in vitro and in animal models, our findings indicate that this cytokine should be examined in clinical studies of DLBCL.
Sarosiek
Kristopher A
KA
Department of Molecular and Cellular Pharmacology, University of Miami, FL, USA.
Malumbres
Raquel
R
Nechushtan
Hovav
H
Gentles
Andrew J
AJ
Avisar
Eli
E
Lossos
Izidore S
IS
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics* / Q000502:physiology; D045744:Cell Line, Tumor; D004318:Doxycycline / Q000008:administration & dosage; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D016259:Genes, myc; D006367:HeLa Cells; D006801:Humans; D007378:Interleukins / Q000008:administration & dosage / Q000494:pharmacology / Q000502:physiology*; D016403:Lymphoma, Large B-Cell, Diffuse / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology*; D051379:Mice; D016513:Mice, SCID; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology; D023041:Xenograft Model Antitumor Assays; D000098546:Interleukin-21
D007378:Interleukins; D000098546:Interleukin-21; D004318:Doxycycline