TY - JOUR
T1 - Acquisition of an immunosuppressive protumorigenic macrophage phenotype depending on c-Jun phosphorylation
AU - Hefetz-Sela, Simona
AU - Stein, Ilan
AU - Klieger, Yair
AU - Porat, Rinnat
AU - Sade-Feldman, Moshe
AU - Zreik, Farid
AU - Nagler, Arnon
AU - Pappo, Orit
AU - Quagliata, Luca
AU - Dazert, Eva
AU - Eferl, Robert
AU - Terracciano, Luigi
AU - Wagner, Erwin F.
AU - Ben-Neriah, Yinon
AU - Baniyash, Michal
AU - Pikarsky, Eli
PY - 2014/12/9
Y1 - 2014/12/9
N2 - 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.
AB - 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.
KW - HCC
KW - M1 macrophages
KW - M2 macrophages
KW - Tregs
KW - c-Jun phosphorylation
UR - http://www.scopus.com/inward/record.url?scp=84916631333&partnerID=8YFLogxK
U2 - 10.1073/pnas.1409700111
DO - 10.1073/pnas.1409700111
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C2 - 25422452
AN - SCOPUS:84916631333
SN - 0027-8424
VL - 111
SP - 17582
EP - 17587
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 49
ER -