Experimental hematology · 2010
Heterogeneous expression and function of IL-21R and susceptibility to IL-21-mediated apoptosis in follicular lymphoma cells.
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de Totero Daniela, Capaia Matteo, Fabbi Marina, Croce Michela, Meazza Raffaella, Cutrona Giovanna, Zupo Simona, Loiacono Fabrizio, Truini Mauro, Ferrarini Manlio, Ferrini Silvano
Аннотация
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.
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.
Предметные рубрики MeSH
ApoptosisCell Line, TumorChromosomes, Human, Pair 14Chromosomes, Human, Pair 18Gene Expression Regulation, NeoplasticHumansInterleukin-21 Receptor alpha SubunitInterleukinsJanus Kinase 3Janus KinasesLymphoma, FollicularNeoplasm ProteinsSTAT Transcription FactorsSignal TransductionSuppressor of Cytokine Signaling 3 ProteinSuppressor of Cytokine Signaling ProteinsTranslocation, GeneticInterleukin-21