Expression of RANTES and MCP-1 in epithelial cells is regulated via LMP1 and CD40.
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-kappaB 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-kappaB. 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.
Buettner
Maike
M
Institute for Pathology, University Hospital of the Friedrich-Alexander-University, Erlangen-Nuremberg, Germany. Maike.Buettner@patho.imed.uni-erlangen.de
Meyer
Birgit
B
Schreck
Sabine
S
Niedobitek
Gerald
G
D019013:CD40 Antigens / Q000378:metabolism*; D002294:Carcinoma, Squamous Cell / Q000378:metabolism* / Q000821:virology; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism*; D018946:Chemokine CCL5 / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006258:Head and Neck Neoplasms / Q000378:metabolism* / Q000821:virology; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D016328:NF-kappa B / Q000378:metabolism; D009856:Oncogene Proteins, Viral / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction; D015854:Up-Regulation; D014763:Viral Matrix Proteins / Q000378:metabolism*
C111835:CCL2 protein, human; D019013:CD40 Antigens; D018932:Chemokine CCL2; D018946:Chemokine CCL5; C037662:EBV-associated membrane antigen, Epstein-Barr virus; D016328:NF-kappa B; D009856:Oncogene Proteins, Viral; D012333:RNA, Messenger; D014763:Viral Matrix Proteins