Concomitant increase of LMP1 and CD25 (IL‐2‐receptor α) expression induced by IL‐10 in the EBV‐positive NK lines SNK6 and KAI3

Abstract

Extranodal, nasal NK/T-cell lymphomas are regularly EpsteinBarr virus (EBV)-positive, with a type II latency pattern, expressing thus EBNA-1 and LMP1. The contribution of EBV to the tumor development is not known. Similarly to normal natural killer (NK) cells, cell lines derived from malignancies with a NK phenotype require IL-2 for in vitro proliferation. In our effort to explore the contribution of EBV, particularly the role of the LMP1 protein, to the pathogenesis of the NK lymphoma we found that its expression, studied in the NK-lines SNK6 and KAI3, depended on the supply of IL-2 or other cytokines. In the absence of IL-2 other cytokines, such as IL-10 and IFN-c, could maintain LMP1, but the cells did not proliferate. When grown in IL-2, the SNK6 cells produced IL-10 and IFN-c, and these cytokines mediated the expression of LMP1. IL-10 treatment enhanced, while IFN-c receptor blocking antibody reduced, the expression of CD25 and CD54 in the EBV-positive, but not in the EBV-negative lines. IL-10 treated cells required lower amount of IL-2 for proliferation compared to the untreated cells. This effect was seen only with the EBVpositive NK lines in which LMP1 and CD25 were concomitantly upregulated. By this mechanism EBV could have an important role in the development of NK lymphoma since the inflammatory component in the tumor tissue can provide these cytokines. ' 2006 Wiley-Liss, Inc.

Epstein-Barr virus–associated lymphoproliferative disorders

“…As in all EBV-associated T-cell lymphoproliferative disorders, the exact mechanism by which EBV gains access and infects T cells has yet to be determined. Similar to normal NK cells and in contrast to infected B cells, EBV-infected NK cells have been found to require IL-2 for growth and proliferation even with the expression of LMP1 and other type II latency proteins [100,101]. Moreover, the reduction in LMP1 levels in treated cell lines does not lead to growth inhibition or apoptosis within the cells [102].…”

“…This, in theory, argues against EBV involvement in the process of transformation and proliferation of the neoplastic T cells [100,101]. One study has suggested, however, that LMP1 may increase the sensitivity of the infected cell to the growth-promoting effects of IL-2 [101].…”

Novel Targets for Natural Killer/T-cell Lymphoma Immunotherapy

“…In addition to competition with favorable cytokines, NKTL releases cytokines that are unfavorable to antitumor cells. NKTL produces IL-10, which enhances its proliferation through the upregulation of IL-2 receptor expression [16]. Because IL-10 robustly suppresses CD8 responses, NKTL would directly inhibit T-cells via IL-10 production.…”

“…NKTL produces IL-10 for its proliferation [16]. Because counteracting IL-10 by using a neutralizing antibody has shown antitumor effects in a melanoma model [71], this treatment would also be an option in NKTL treatment.…”

Soluble ICAM-1 secretion and its functional role as an autocrine growth factor in nasal NK/T cell lymphoma cells

“…We have previously shown that SNK6 cells produce several cytokines and chemokines such as interferon (IFN)-γ, interleukin (IL)-9, IL-10 and interferon-γ-inducible protein (IP)-10, which play roles in cellular proliferation and invasion in an autocrine manner [7][8][9]. Furthermore, monocytes attracted by IP-10 enhance the proliferation via cell-to-cell contact [10].…”