Expression of RANTES and MCP‐1 in epithelial cells is regulated via LMP1 and CD40

Abstract

Epstein-Barr virus (EBV)-associated undifferentiated nasopharyngeal carcinoma (NPC) is characterized by a prominent nonneoplastic lymphoid stroma. The functional role of these inflammatory cells and the mechanism of their recruitment are not fully understood. In B-cells, the EBV-encoded latent membrane protein 1 (LMP1) can induce the expression of chemokines in an NF-jB dependent manner. We now show that LMP1 can induce the expression of RANTES and MCP-1 in an epithelial cell line, and that this effect is partially reversible by an inhibitor of NF-jB. Since tumor cells of virtually all NPCs show CD40 expression while many cases are LMP1-negative at the protein level, we also investigated the effect of CD40 signaling and demonstrate that CD40 stimulation can transiently induce RANTES and MCP-1 expression in LMP1-negative epithelial cells. In in situ hybridization only rare tumor cells showed expression of these chemokines unrelated to LMP1 expression, a pattern consistent with transient induction through CD40 signaling. Since RANTES and MCP-1 were also detected in the neoplastic cells of oral squamous cell carcinomas lacking a lymphoid stroma it remains uncertain to what extent these CC chemokines contribute to the attraction of inflammatory cells into the NPC microenvironment. ' 2007 Wiley-Liss, Inc.

Detection of Epstein–Barr virus DNA in peripheral blood is associated with the development of bronchiolitis obliterans syndrome after lung transplantation

“…thase (iNOS) in vitro. [19][20][21][22][23] Interestingly, the levels of IL-8, IL-12, RANTES and MCP-1 are increased in the BAL of LTR with BOS 24,25 and the expression of iNOS is elevated. 26 Possibly, EBV contributes to the development of BOS by inducing the production of these cytokines.…”

Epstein-Barr Virus Type 2 Latently Infects T Cells, Inducing an Atypical Activation Characterized by Expression of Lymphotactic Cytokines

“…Production of lymphotactic cytokines has been hypothesized to be a strategy used by EBV to recruit additional lymphocyte targets during infection to enhance the establishment of a persistent infection (51). Indeed, EBV LMP-1, which was detected at all time points studied during EBV-2 T-cell infection, has been shown to upregulate production of IL-8, RANTES, and MIP-1␣ (52)(53)(54)(55). Whether LMP-1 is directly responsible for the high levels of these cytokines observed in EBV-2-infected T-cell cultures and how expression of the cytokines affects the infectious process in vivo have yet to be determined.…”

Epstein-Barr Virus Lytic Transactivator Zta Enhances Chemotactic Activity through Induction of Interleukin-8 in Nasopharyngeal Carcinoma Cells

“…Expression of several chemokines has been demonstrated in NPC tumors, including IL-8, macrophage inflammatory proteins (MIPs), macrophage chemoattractant proteins (MCPs), and RANTES (11,70,75). Considering that EBV may promote chemokine production in B lymphocytes (49), an issue is raised as to how EBV infection of the epithelial tumor cells contributes to the production of chemokines and the recruitment of leukocytes in NPC.…”

“…Previous studies have focused on the effects of EBV latent infection and revealed that viral latent membrane protein 1 (LMP1) is a chemokine inducer. LMP1 can upregulate IL-8, RANTES, and MCP-1 in epithelial cells, mainly through a NF-B-mediated mechanism (11,22,75). Since LMP1 pro-tein is not always detected in NPC biopsies (23,76), it is worth examining whether other EBV gene products may be also involved in the regulation of chemokines.…”