Acquisition of an immunosuppressive protumorigenic macrophage phenotype depending on c-Jun phosphorylation

Simona Hefetz-Sela, Ilan Stein, Yair Klieger, Rinnat Porat, Moshe Sade-Feldman, Farid Zreik, Arnon Nagler, Orit Pappo, Luca Quagliata, Eva Dazert, Robert Eferl, Luigi Terracciano, Erwin F. Wagner, Yinon Ben-Neriah, Michal Baniyash, Eli Pikarsky*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

46 Scopus citations


The inflamed tumor microenvironment plays a critical role in tumorigenesis. However, the mechanisms through which immune cells, particularly macrophages, promote tumorigenesis have only been partially elucidated, and the full scope of signaling pathways supplying macrophages with protumorigenic phenotypes still remain largely unknown. Here we report that germ-line absence of c-Jun N-terminal phosphorylation at serines 63 and 73 impedes inflammation-associated hepatocarcinogenesis, yet deleting c-Jun only in hepatocytes does not inhibit hepatocellular carcinoma (HCC) formation. Moreover, in human HCC-bearing livers, c-Jun phosphorylation is found in inflammatory cells, whereas it is mostly absent from malignant hepatocytes. Interestingly, macrophages in livers of mice with chronic hepatitis gradually switch their phenotype along the course of disease. Macrophage phenotype and density are dictated by c-Jun phosphorylation, in vitro and in vivo. Transition of macrophage phenotype, from antitumorigenic to protumorigenic, occurs before tumorigenesis, resulting in the production of various chemokines, including chemokine (C-C motif) ligand 17 (CCL17) and CCL22. Such signals, emanating from the liver microenvironment, direct the recruitment of regulatory T cells, which are known to facilitate HCC growth.Our findings identify c-Jun phosphorylation as a key mediator of macrophage education and point to the recruitment of immunosuppressive regulatory T cells as a possible protumorigenic mechanism.

Original languageAmerican English
Pages (from-to)17582-17587
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number49
StatePublished - 9 Dec 2014


  • HCC
  • M1 macrophages
  • M2 macrophages
  • Tregs
  • c-Jun phosphorylation


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