title: CCAAT/enhancer binding protein δ in macrophages contributes to immunosuppression and inhibits phagocytosis in nasopharyngeal carcinoma.
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 (PGE₂) led to the production and activity of the transcription factor CCAAT/enhancer binding protein δ (C/EBPδ) by stimulating the nucleocytoplasmic shuttling of the RNA binding protein Hu antigen R (HuR), which bound to and stabilized CEBPD mRNA in macrophages. An increase in C/EBPδ 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.
authors.affiliation: Institute of Bioinformatics and Biosignal Transduction, National Cheng Kung University, Tainan 701, Taiwan, ROC.
authors.forename: Yu-Wei
authors.initials: YW
authors.lastname: Hsiao
authors.forename: Chien-Feng
authors.initials: CF
authors.lastname: Li
authors.forename: Jhih-Ying
authors.initials: JY
authors.lastname: Chi
authors.forename: Joseph T
authors.initials: JT
authors.lastname: Tseng
authors.forename: Yao
authors.initials: Y
authors.lastname: Chang
authors.forename: Li-Jin
authors.initials: LJ
authors.lastname: Hsu
authors.forename: Chien-Hsun
authors.initials: CH
authors.lastname: Lee
authors.forename: Tsung-Hao
authors.initials: TH
authors.lastname: Chang
authors.forename: Shao-Ming
authors.initials: SM
authors.lastname: Wang
authors.forename: Dennis Ding Hwa
authors.initials: DD
authors.lastname: Wang
authors.forename: Hung-Chi
authors.initials: HC
authors.lastname: Cheng
authors.forename: Ju-Ming
authors.initials: JM
authors.lastname: Wang
mesh_terms: D002097:C-Reactive Protein / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D051743:CCAAT-Enhancer-Binding Protein-delta / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D002277:Carcinoma; D015232:Dinoprostone / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D051959:ELAV Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007108:Immune Tolerance; D016753:Interleukin-10 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D008264:Macrophages / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D000077274:Nasopharyngeal Carcinoma; D009303:Nasopharyngeal Neoplasms / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D010587:Phagocytosis; D020871:RNA Stability / Q000235:genetics / Q000276:immunology; D012333:RNA, Messenger / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D000683:Serum Amyloid P-Component / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D020298:U937 Cells; D000099153:Pentraxins
chemical_list: D002097:C-Reactive Protein; D051743:CCAAT-Enhancer-Binding Protein-delta; D015232:Dinoprostone; D051959:ELAV Proteins; D016753:Interleukin-10; D012333:RNA, Messenger; D000683:Serum Amyloid P-Component; D000099153:Pentraxins; C497252:CEBPD protein, human; C508609:IL10 protein, human