Heterogeneous expression and function of IL-21R and susceptibility to IL-21-mediated apoptosis in follicular lymphoma cells.

Abstract

OBJECTIVE:

Interleukin (IL)-21, a member of the IL-2 family, has antitumor activity and is now being tested in non-Hodgkin's lymphoma in combination with anti-CD20 antibodies. IL-21 may either induce apoptosis or promote growth in different lymphoid malignancies. We therefore investigated the IL-21/IL-21R system in follicular lymphoma (FL) cells.

MATERIALS AND METHODS:

IL-21R expression was studied by reverse transcription polymerase chain reaction, immunofluorescence, and Western blot analyses. Apoptosis was measured by Annexin-V-propidium iodide staining. Signaling via IL-21R was studied using antibodies specific for phosphorylated Janus-activating kinase and signal transducers and activators of transcription proteins by Western Blot.

RESULTS:

IL-21R was found on primary FL cells in 15 of 15 cases at diagnosis and IL-21 increased apoptosis in 10 of 10 FL samples. However, cells from areas of diffuse growth in FL and from two diffuse lymphomas evolved from previous FL, showed low IL-21R expression. The latter were also resistant to IL-21-mediated apoptosis. Among lymphoma cell lines bearing the t(14;18) translocation, only 1 of 7 showed increased apoptosis in response to IL-21 stimulation. This cell line was IL-21R-positive, whereas five of six nonresponsive cell lines showed very low IL-21R expression. Intriguingly, one of the IL-21-resistant cell lines (DOHH2) expressed high levels of IL-21R. Treatment with IL-21 or IL-4 upregulated suppressor of cytokine signaling 3 gene expression in the IL-21-responsive cell line, but not in DOHH2 cells, which showed defective Janus-activating kinase/signal transducers and activators of transcription signaling in response to IL-21, in relationship to the lack of Janus-activating kinase 3 gene expression.

CONCLUSION:

These data indicate that low IL-21R expression or defective signal transduction downstream IL-21R may cause refractoriness to IL-21-mediated effects in some FL cells.

• Authors: Daniela de Totero, Matteo Capaia, Marina Fabbi, Michela Croce, Raffaella Meazza, Giovanna Cutrona, Simona Zupo, Fabrizio Loiacono, Mauro Truini, Manlio Ferrarini, Silvano Ferrini
• Journal: Experimental hematology (Exp Hematol) Vol. 38 Issue 5 Pg. 373-83 (May 2010) ISSN: 1873-2399 [Electronic] Netherlands
• PMID: 20193734 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: 2010 ISEH-Society for Hematology and Stem Cells. Published by Elsevier Inc. All rights reserved.

Chemical References

• IL21R protein, human
• Interleukin-21 Receptor alpha Subunit
• Interleukins
• Neoplasm Proteins
• SOCS3 protein, human
• STAT Transcription Factors
• Suppressor of Cytokine Signaling 3 Protein
• Suppressor of Cytokine Signaling Proteins
• JAK3 protein, human
• Janus Kinase 3
• Janus Kinases
• interleukin-21

Topics

• Apoptosis (drug effects)
• Cell Line, Tumor (cytology, drug effects)
• Chromosomes, Human, Pair 14 (ultrastructure)
• Chromosomes, Human, Pair 18 (ultrastructure)
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Interleukin-21 Receptor alpha Subunit (biosynthesis, drug effects, physiology)
• Interleukins (pharmacology, physiology)
• Janus Kinase 3 (deficiency)
• Janus Kinases (physiology)
• Lymphoma, Follicular (genetics, pathology)
• Neoplasm Proteins (biosynthesis, genetics, physiology)
• STAT Transcription Factors (physiology)
• Signal Transduction (drug effects)
• Suppressor of Cytokine Signaling 3 Protein
• Suppressor of Cytokine Signaling Proteins (biosynthesis, genetics)
• Translocation, Genetic