CCAAT/Enhancer binding protein d in macrophages contributes to immunosuppression and inhibits phagocytosis in nasopharyngeal carcinoma

Yu Wei Hsiao, Chien Feng Li, Jhih Ying Chi, Joseph T. Tseng, Yao Chang, Li Jin Hsu, Chien Hsun Lee, Tsung Hao Chang, Shao Ming Wang, Dennis Ding Hwa Wang, Hung Chi Cheng, Ju Ming Wang

Research output: Contribution to journalArticlepeer-review

20 Citations (Scopus)

Abstract

Although tumors tend to be associated with immune cells and inflammation, this immune response often fails to eliminate the cancer and instead promotes cancer progression. Tumor-associated macrophages (TAMs) fail to phagocytose tumor cells, and they also produce signals that suppress the adaptive immune response. We showed that immunosuppressive prostaglandin E2 (PGE 2) led to the production and activity of the transcription factor CCAAT/enhancer binding protein d (C/EBPd) by stimulating the nu-cleocytoplasmic shuttling of the RNA binding protein Hu antigen R (HuR), which bound to and stabilized CEBPD mRNA in macrophages. An increase in C/EBPd abundance in macrophages in response to PGE2 resulted in enhanced production of the immunosuppressive cytokine interleukin-10 (IL-10) and of pentraxin 3 (PTX3), which suppresses the ability of macrophages to phagocytose tumor cells. Furthermore, conditioned medium from C/EBPδ-replete, but not C/EBPδ-deficient, macrophages inhibited the phagocytosis of tumor cells by macrophages, suggesting an autocrine mode of regulation. Immunohistochemical analysis demonstrated that the amount of cytosolic HuR protein correlated with increased C/EBPδ abundance in TAMs in malignant nasopharyngeal carcinoma. Together, these data suggest that the inflammatory PGE2-HuR-C/ EBPδ axis in macrophages promotes tumor progression by preventing the phagocytosis of tumor cells and inducing immunosuppressive cytokine production.

Original languageEnglish
Article numberra59
JournalScience Signaling
Volume6
Issue number284
DOIs
Publication statusPublished - 2013 Jul 16

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Cell Biology
  • Molecular Biology

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