The Epstein–Barr Virus Latent Membrane Protein 1 Induces Interleukin-10 in Burkitt's Lymphoma Cells but Not in Hodgkin's Cells Involving the p38/SAPK2 Pathway

Abstract

Infection of B cells with Epstein-Barr Virus (EBV) induces interleukin-10 (IL-10) production, which may contribute to transformation. IL-10 can modulate the immune response at certain levels, playing a crucial role in balancing humoral and cellular responses. Moreover, it can function as a growth and differentiation factor for B cells. However, the mechanism of IL-10 induction is still unclear. Here we demonstrate that IL-10 was specifically induced by the EBV-latent membrane protein 1 (LMP1) in Burkitt's lymphoma (BL) cell lines BL2 and BL41. In two T cell lines (Jurkat, MOLT3), two NHL cell lines (U266, MHH-PREB1), or three Hodgkin's disease (HD) cell lines (L428, L540, and KMH2), LMP1 did not induce IL-10 expression. In contrast, LMP1 activated CD40 or CD54 (ICAM1) expression in the analyzed cell lines. LMP1 derivatives lacking the C-terminal activation regions (CTAR), by deletion of the amino acids between 187 and 351 (Delta CTAR1) or 232 and 386 (Delta CTAR2), alone, or together induced IL-10 at very low amounts compared to wild-type LMP1. Inhibition of LMP1-mediated NF kappa B activation by constitutive repressive I kappa B-alpha only marginally impaired IL-10 expression in BL2 cells, while SB2035080 at 5 microM (a specific p38/SAPK2 inhibitor) led to reduced IL-10 expression. Our findings confirm the role of LMP1 in transactivation of cellular genes possibly important for tumor immunoescape but show that more than one signaling pathway is involved in this activation and suggests the necessity of a defined conformation of CTARs to activate IL-10 involving p38/SAPK2.

Rituximab inhibits p38 MAPK activity in 2F7 B NHL and decreases IL-10 transcription: Pivotal role of p38 MAPK in drug resistance

“…This inhibition causes a decrease in the constitutively activated STAT3, downregulation of Bcl-2 expression and the tumor cells become sensitive to apoptotic stimuli, including the effect of various chemotherapeutic drugs . Previous reports showed that IL-10 regulation is via p38 MAPK activity (Ma et al, 2001;Vockerodt et al, 2001). We hypothesized, therefore, that p38 MAPK may regulate IL-10 synthesis in the 2F7 cell line.…”

“…It has been reported that IL-10 induction is accompanied by an enhanced phosphorylation of p38/SAPK2 in the Burkitt's lymphoma cell line BL2 (Vockerodt et al, 2001). Other studies have shown that activation of the mitogen-activated protein kinase (MAPK) signaling pathway regulates the activation of Sp1, which in turn regulates the transcription of the hIL-10 gene (Pedersen et al, 2002).…”

Nuclear Factor κB-Dependent Activation of the Antiapoptoticbfl-1Gene by the Epstein-Barr Virus Latent Membrane Protein 1 and Activated CD40 Receptor

“…However, in this case, the contribution of this sequence motif is dependent on the NF-B-like binding site at Ϫ52/Ϫ43, since any promoter fragments that lack the latter are not responsive to LMP1. It has also been shown that the mitogen-activated protein kinase p38 and NF-B contribute to the transactivation of certain LMP-1-inducible genes, such as IL-6, IL-8, and IL-10, through coregulation of their promoter sequences (33,116). In a preliminary experiment, however, a well-established and specific inhibitor of p38 activation (SB203580) (112) did not affect transactivation of the bfl-1 promoter by LMP1 in DG75 cells (result not shown).…”

Epstein-Barr Virus Lytic Infection Contributes to Lymphoproliferative Disease in a SCID Mouse Model

“…For example, IL-6 enhances the growth of LCLs in mouse models of LPD (48,55), and some freshly explanted cells from EBV-positive LPD are dependent on autocrine/paracrine secretion of IL-10 for growth and survival (30). Three different EBV gene products, including the latent LMP1 and EBVencoded RNA gene products and the IE lytic protein, BZLF1, have been reported to induce expression of cellular IL-10 (cIL-10) (28) (24,60). EBV also encodes a lytic viral homolog of IL-10, vIL-10 (16), which likewise enhances the growth of B cells (46).…”