Interleukin-21 effectively induces apoptosis in mantle cell lymphoma through a STAT1-dependent mechanism.

Abstract

Interleukin-21 (IL-21) has been recently shown to modulate the growth of specific types of B-cell neoplasm. Here, we studied the biological effects of IL-21 in mantle cell lymphoma (MCL). All MCL cell lines and tumors examined expressed the IL-21 receptor. Addition of recombinant IL-21 (rIL-21) in vitro effectively induced STAT1 activation and apoptosis in MCL cells. As STAT1 is known to have tumor-suppressor functions, we hypothesized that STAT1 is important in mediating IL-21-induced apoptosis in MCL cells. In support of this hypothesis, inhibition of STAT1 expression using siRNA significantly decreased the apoptotic responses induced by IL-21. To further investigate the mechanism of IL-21-mediated apoptosis, we employed oligonucleotide arrays to evaluate changes in the expression of apoptosis-related genes induced by rIL-21; rIL-21 significantly upregulated three proapoptotic proteins (BIK, NIP3 and HARAKIRI) and downregulated two antiapoptotic proteins (BCL-2 and BCL-XL/S) as well as tumor necrosis factor-alpha. Using an ELISA-based assay, we demonstrated that rIL-21 significantly decreased the DNA binding of nuclear factor-kappaB, a transcriptional factor known to be a survival signal for MCL cells. To conclude, IL-21 can effectively induce apoptosis in MCL via a STAT1-dependent pathway. Further understanding of IL-21-mediated apoptosis in MCL may be useful in designing novel therapeutic approaches for this disease.

• Authors: P Gelebart, Z Zak, M Anand, J Dien-Bard, H M Amin, R Lai
• Journal: Leukemia (Leukemia) Vol. 23 Issue 10 Pg. 1836-46 (Oct 2009) ISSN: 1476-5551 [Electronic] England
• PMID: 19494838 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Interleukins
• NF-kappa B
• RNA, Messenger
• RNA, Small Interfering
• Receptors, Interleukin-21
• Recombinant Proteins
• STAT1 Transcription Factor
• STAT1 protein, human
• interleukin-21

Topics

• Apoptosis (drug effects)
• Blotting, Western
• Flow Cytometry
• Fluorescent Antibody Technique
• Gene Expression Profiling
• Humans
• Immunoblotting
• Interleukins (pharmacology)
• Lymphoma, Mantle-Cell (genetics, metabolism, pathology)
• Membrane Potential, Mitochondrial
• NF-kappa B (genetics, metabolism)
• Oligonucleotide Array Sequence Analysis
• RNA, Messenger (genetics, metabolism)
• RNA, Small Interfering (pharmacology)
• Receptors, Interleukin-21 (genetics, metabolism)
• Recombinant Proteins (pharmacology)
• Reverse Transcriptase Polymerase Chain Reaction
• STAT1 Transcription Factor (antagonists & inhibitors, genetics, metabolism)
• Tumor Cells, Cultured