Su Z, Yang R, Zhang W, Xu L, Zhong Y, Yin Y, Cen J, DeWitt J P, Wei Q
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.
Department of Biochemistry and Molecular Biology, Beijing Normal University, Gene Engineering and Biotechnology Beijing Key Laboratory, Beijing, PR China.
Cell Death Dis. 2015 May 7;6(5):e1740. doi: 10.1038/cddis.2015.92.
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.
巨噬细胞参与肿瘤的生长和进展。它们浸润到肿瘤中并引发炎症，从而营造出有利于肿瘤生长和转移的微环境。然而，某些刺激可能会诱导巨噬细胞成为肿瘤终结者。在此我们报告，钙调神经磷酸酶B亚基（CnB）与干扰素-γ协同作用，使巨噬细胞对癌细胞具有高度细胞毒性。此外，CnB和干扰素-γ协同作用，将小鼠肿瘤相关巨噬细胞以及人单核细胞衍生的巨噬细胞极化为M1样表型。这种协同作用由CnB参与的整合素αM-p38丝裂原活化蛋白激酶信号与干扰素-γ启动的p38/蛋白激酶C-δ/Janus激酶2信号之间的串扰介导。有趣的是，信号转导及转录激活因子1（STAT1）是协调CnB和干扰素-γ协同作用的关键因子，STAT1第727位丝氨酸和第701位酪氨酸的磷酸化状态直接受CnB和干扰素-γ调控。
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