- 作者：Daniela de Totero ; Matteo Capaia ; Marina Fabbi ; Michela Croce ; Raffaella Meazza ; Giovanna Cutrona ; Simona Zupo ; Fabrizio Loiacono ; Mauro Truini ; Manlio Ferrarini ; Silvano Ferrini
- 刊名：Experimental Hematology
- 出版年：2010
- 出版时间：May 2010
- 年：2010
- 卷：38
- 期：5
- 页码：373-383
- 全文大小：1163 K
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.