Lymphotoxin acts as an autocrine growth factor for Epstein‐Barr virus‐transformed B cells and differentiated Burkitt lymphoma cell lines

Abstract

A critical event in B cell immortalization by Epstein-Barr virus (EBV) is the establishment of an autocrine loop where cells produce a growth factor which supports their own proliferation. We investigated the potential of lymphoblastoid cell lines (LCL) and Burkitt lymphoma (BL) cell lines to produce and respond to the cytotoxins, tumor necrosis factor-alpha (TNF-alpha) and lymphotoxin (LT). Transformation in vitro of peripheral blood B cells by EBV from seven different donors resulted in spontaneous production of both LT (11,542 pg/ml +/- 7546, mean +/- SD) and, to a lesser extent, TNF-alpha (197 pg/ml +/- 174). Similarly BL cell lines derived from in vivo transformation which developed a 'LCL-like' phenotype in vitro (group III) produced more LT (1990 pg/ml +/- 1740) than the 'group I' BL cell lines (< 40 pg/ml LT) which had maintained the original BL biopsy cell phenotype in vitro. Transformation of peripheral blood B cells to generate LCL also resulted in an increase in surface p75 (p < 0.02) and to a lesser extent p55 (not significant, ns) TNF receptor (TNF-R) expression. Similar increases in surface TNF-R (p75 p < 0.02, p55 ns) were observed on the 'group III' BL cell lines compared with the 'group I' BL cell lines. Proliferation of an LCL and a 'group III' BL cell line in vitro was via an autocrine loop since inhibition of LT reduced proliferation. This proliferation could also be blocked in the presence of the antagonistic anti-p55 TNF-R antibody, H398, but not the antagonistic antibody anti-p75 TNF-R antibody UTR-1. Furthermore, proliferation could be induced with the p55 agonistic antibody, HTR-9. In contrast to these observations with p55 TNF-R antibodies, two out of six of the 'group III' BL lines (Jijoye and Oba) only expressed the p75 TNF-R and proliferation of these cells could only be blocked by the antagonistic anti-p75 TNF-R antibody UTR-1. These data suggest that LT is an autocrine growth factor for lymphoblastoid cells, and BL cell lines which display an LCL phenotype. Furthermore, although both TNF-R are increased on the surface of these cells, this autocrine growth signal is mediated principally through binding to the p55 TNF-R.

Host Immune Responses in the Course of Bovine Leukemia Virus Infection.

“…It is important to examine what caused the downregulation of the level of TNF RI expressions, and whether this was specific to BLV-infected cells. The change of TNF RI/RII expression patterns has also been shown in other B cell leukemia cases including chronic lymphocyte leukemia and Burkitt lymphoma, and these consequence for the proliferative effects of TNF α [13,65]. Then, we examined the proliferative responses of these sheep PBMC against TNF α stimulation.…”

“…On one hand, TNF α may play an important role to eliminate some infectious agents, such as Toxioplasma gondii and Human immunodeficiency virus [4,6,9,12,15]. On the other hand, its function may promote disease progression [13,16,60]. The roles of TNF α in the course of BLV infection have not been fully established.…”

“…For example, several studies have shown that the individuals who produced more TNFα against malaria infection, showed a tendency to progress to severe symptoms [28,37]. Furthermore, TNF α is thought to be one of the cytokines, which contributes to the control of B cell death [1,30], the virus-induced B cell proliferation [10,13,34], and the leukemogenesis of B-1 cells [14,65,66]. Conflicting activities of TNF α, including induction and suppression of apoptosis have been introduced mainly through two distinct TNFreceptors; TNF RI and TNF RII [11,15,17].…”

Immunohistochemical Analysis of Expression Patterns of Tumor Necrosis Factor Receptors on Lymphoma Cells in Enzootic Bovine Leukosis

“…Furthermore, TNF-α plays a critical role in the elimination of some infectious agents [21]. On the other hand, its function may promote disease progression [11,12]. TNF-α activity is mediated by two functionally different cell surface receptors, TNF-RI and TNF-RII [34].…”

“…Most biologic responses of TNF-α, such as the induction and suppression of apoptosis, are considered to be mediated by these two different receptors [10,11,35,36,41]. Some investigations have revealed the relationships between TNF-α or its receptors and B-cell malignant transformations such as in the case of chronic lymphocytic leukemia [38,41], Epstein-Barr (EB) virus-transformed B cells, and Burkitt lymphoma [11]. In these lymphomas, TNF-α is involved in the proliferation of leukemic cells through its binding to TNF-RII.…”