Selected IL-21R Expression and Apoptosis Induction by IL-21 in Follicular Lymphoma.

Abstract

Abstract IL-21 receptor (IL-21R), a member of the common gamma receptor family, is expressed on many kind cells including T-cells, B-cells, and NK cells. IL-21 promotes the proliferation and maturation of NK cells and shows anti-tumor activities in animal systems. Although these results suggest its clinical use in the treatment of malignancies, it has also been shown that IL-21 may conversely accelerate the proliferation of IL-21R-expressing tumor cells. Considering the potential for therapeutic application of recombinant IL-21, we examined IL-21R expression and response to IL-21 in hematological malignancies. Using flow cytometry, we examined IL-21R expression in primary samples from AML, ALL, B-CLL, B-NHL and adult T-cell leukemia/lymphoma (ATLL) caused by a retrovirus, HTLV-1. Among 35 primary samples, only 5 samples from 16 patients with B-NHL and one sample from 8 patients with ATL were IL-21R positive. Of note, all the IL-21R positive NHL also expressed CD10, one of the marker molecules of follicular center cells. Indeed, two of the five patients were diagnosed follicular lymphoma with t(14;18)(q32;q21). Corresponding to these results, the follicular lymphoma cell line SUDHL-4 and most ATLL and HTLV-1-infected cell lines were IL-21R positive. Interestingly, IL21 showed dual effects on these cell lines; IL-21 stimulated the proliferation of ATLL cell lines but suppressed the proliferation of SUDHL-4. Annexin V and propidium iodide staining for detection of early and late apoptosis and mitochondrial membrane potential analysis indicated that the suppression was the result of apoptosis. Exposure of SUDHL-4 to IL-21 resulted in significant time-dependent induction of caspase-8 and caspase-3 activation. More importantly, IL-21 decreased Bcl-2 expression but drastically increased Bax expression. Thus, selected expression of IL-21R in follicular lymphoma cells and induction of apoptosis by IL-21 provide a strong background for IL-21 as an anti-neoplastic agent at least in a subset of follicular lymphoma.