title: The synergistic interaction between the calcineurin B subunit and IFN-γ enhances macrophage antitumor activity.
abstract: Macrophages are involved in tumor growth and progression. They infiltrate into tumors and cause inflammation, which creates a microenvironment favoring tumor growth and metastasis. However, certain stimuli may induce macrophages to act as tumor terminators. Here we report that the calcineurin B subunit (CnB) synergizes with IFN-γ to make macrophages highly cytotoxic to cancer cells. Furthermore, CnB and IFN-γ act synergistically to polarize mouse tumor-associated macrophages, as well as human monocyte-derived macrophages to an M1-like phenotype. This synergy is mediated by the crosstalk between CnB-engaged integrin αM-p38 MAPK signaling and IFN-γ-initiated p38/PKC-δ/Jak2 signaling. Interestingly, the signal transducer and activator of transcription 1 (STAT1) is a key factor that orchestrates the synergy of CnB and IFN-γ, and the phosphorylation status at Ser727 and Tyr701 of STAT1 is directly regulated by CnB and IFN-γ.
authors.affiliation: 1] Department of Biochemistry and Molecular Biology, Beijing Normal University, Gene Engineering and Biotechnology Beijing Key Laboratory, Beijing, PR China [2] Department of Biochemistry and Molecular Biology, Medical School, Southeast University, Nanjing, Jiangsu, PR China [3] Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Z
authors.initials: Z
authors.lastname: Su
authors.affiliation: Department of Biochemistry and Molecular Biology, Beijing Normal University, Gene Engineering and Biotechnology Beijing Key Laboratory, Beijing, PR China.
authors.forename: R
authors.initials: R
authors.lastname: Yang
authors.affiliation: Department of Biochemistry and Molecular Biology, Beijing Normal University, Gene Engineering and Biotechnology Beijing Key Laboratory, Beijing, PR China.
authors.forename: W
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Department of Biochemistry and Molecular Biology, Beijing Normal University, Gene Engineering and Biotechnology Beijing Key Laboratory, Beijing, PR China.
authors.forename: L
authors.initials: L
authors.lastname: Xu
authors.affiliation: Department of Biochemistry and Molecular Biology, Beijing Normal University, Gene Engineering and Biotechnology Beijing Key Laboratory, Beijing, PR China.
authors.forename: Y
authors.initials: Y
authors.lastname: Zhong
authors.affiliation: Department of Biochemistry and Molecular Biology, Beijing Normal University, Gene Engineering and Biotechnology Beijing Key Laboratory, Beijing, PR China.
authors.forename: Y
authors.initials: Y
authors.lastname: Yin
authors.affiliation: Department of Biochemistry and Molecular Biology, Beijing Normal University, Gene Engineering and Biotechnology Beijing Key Laboratory, Beijing, PR China.
authors.forename: J
authors.initials: J
authors.lastname: Cen
authors.affiliation: Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: J P
authors.initials: JP
authors.lastname: DeWitt
authors.affiliation: Department of Biochemistry and Molecular Biology, Beijing Normal University, Gene Engineering and Biotechnology Beijing Key Laboratory, Beijing, PR China.
authors.forename: Q
authors.initials: Q
authors.lastname: Wei
mesh_terms: D000818:Animals; D039481:CD11b Antigen / Q000378:metabolism; D019703:Calcineurin / Q000494:pharmacology*; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008264:Macrophages / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D010766:Phosphorylation / Q000187:drug effects; D000067996:RAW 264.7 Cells; D011897:Random Allocation; D011994:Recombinant Proteins / Q000494:pharmacology; D050794:STAT1 Transcription Factor / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D039481:CD11b Antigen; D011994:Recombinant Proteins; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D007371:Interferon-gamma; D048051:p38 Mitogen-Activated Protein Kinases; D019703:Calcineurin