Interleukin‐2 induces NF‐κB activation through BCL10 and affects its subcellular localization in natural killer lymphoma cells

Abstract

Deregulation of nuclear factor (NF)-kappaB signalling is common in cancers and is essential for tumourigenesis. Constitutive NF-kappaB activation in extranodal natural killer (NK)-cell lymphoma, nasal type (ENKL) is known to be associated with aberrant nuclear translocation of BCL10. Here we investigated the mechanisms leading to NF-kappaB activation and BCL10 nuclear localization in ENKLs. Given that ENKLs are dependent on T-cell-derived interleukin-2 (IL2) for cytotoxicity and proliferation, we investigated whether IL2 modulates NF-kappaB activation and BCL10 subcellular localization in ENKLs. In the present study, IL2-activated NK lymphoma cells were found to induce NF-kappaB activation via the PI3K/Akt pathway, leading to an increase in the entry of G(2)/M phase and concomitant transcription of NF-kappaB-responsive genes. We also found that BCL10, a key mediator of NF-kappaB signalling, participates in the cytokine receptor-induced activation of NF-kappaB. Knockdown of BCL10 expression resulted in deficient NF-kappaB signalling, whereas Akt activation was unaffected. Our results suggest that BCL10 plays a role downstream of Akt in the IL2-triggered NF-kappaB signalling pathway. Moreover, the addition of IL2 to NK cells led to aberrant nuclear translocation of BCL10, which is a pathological feature of ENKLs. We further show that BCL10 can bind to BCL3, a transcriptional co-activator and nuclear protein. Up-regulation of BCL3 expression was observed in response to IL2. Similar to BCL10, the expression and nuclear translocation of BCL3 were induced by IL2 in an Akt-dependent manner. The nuclear translocation of BCL10 was also dependent on BCL3 because silencing BCL3 by RNA interference abrogated this translocation. We identified a critical role for BCL10 in the cytokine receptor-induced NF-kappaB signalling pathway, which is essential for NK cell activation. We also revealed the underlying mechanism that controls BCL10 nuclear translocation in NK cells. Our findings provide insight into a molecular network within the NF-kappaB signalling pathway that promotes the pathogenesis of NK cell lymphomas.

Genetic Variants in Interleukin-2 and Risk of Lymphoma among Children in Korea

“…As a growth factor for T cells and natural killer (NK) cells, IL2 activated lymphoma cells and IL2 levels affected the Hodgkin lymphoma risk (Skinnider et al 2002;Cozen et al, 2008;Chan et al, 2010). Although IL2 rs2069762 in our study was not associated with increased risk of NHL in a pooled analysis, the rs2069762 was associated with follicular lymphoma (FL) survival in adult (Rothman et al, 2006;Cerhan et al, 2007).…”

Expression of Epstein-Barr Virus–Encoded Proteins in Extranodal NK/T-cell Lymphoma, Nasal Type (ENKL): Differences in Biologic and Clinical Behaviors of LMP1-Positive and -Negative ENKL

“…We confirmed that LMP1 expression in ENKL was correlated with both nuclear localization of RelA and detection of phosphorylated Akt. Indeed, the activation of NF-kB and phosphorylation of Akt in ENKL cells has mainly been discussed in relation to stimulation effects of cytokines such as IL-2 and IL-15 (29,30). Although environmental factors may exert a supportive role in the activation of NF-kB and phosphorylation of Akt, RNAi for LMP1 in Hank1 cells confirmed a major effect of LMP1 on these events in ENKL cells.…”

Evidence for Alteration of EZH2, BMI1, and KDM6A and Epigenetic Reprogramming in Human Papillomavirus Type 16 E6/E7-Expressing Keratinocytes

“…For total cell lysates and nuclear fractions, monolayers were extracted as previously described (10,26), and protein concentrations were determined using the bicinchoninic acid (BCA) protein assay reagent (Pierce, Rockford, IL). For blots, 60 g or 100 g of the appropriate lysate was subjected to SDS-PAGE according to the Laemmli method.…”