Dataset Information

Protumoral TSP50 Regulates Macrophage Activities and Polarization via Production of TNF-? and IL-1?, and Activation of the NF-?B Signaling Pathway.

ABSTRACT: Testes-specific protease 50 (TSP50) is abnormally overexpressed in many kinds of cancers and promotes cell proliferation and migration. However, whether TSP50 can influence the tumor microenvironment, especially the function of immune cells in the microenvironment, remains largely unknown. We demonstrated that exposure to the conditioned medium from TSP50-overexpressing cells, or co-culture with TSP50-overexpressing cells, enhanced the cytokine production and phagocytic activities of macrophages, and induced M2b polarization. Further investigation showed that production of TNF-? and IL-1? was strongly induced by TSP50 in TSP50-overexpressing cells. TSP50-induced TNF-? and IL-1? were main factors that mediated the effects of TSP50-overexpressing cells on macrophages. The NF-?B pathway could be activated in macrophages upon the treatment of conditioned medium of TSP50-overexpressing cells and its activation is necessary for the observed effects on macrophages. Taken together, our results suggested that oncogenic TSP50 expressed in cells could activate surrounding macrophages and induce M2b polarization, partly through inducing TNF-?/ IL-1? secretion and subsequent NF-?B pathway activation. This implies a potential mechanism by which oncogene TSP50 regulates tumor microenvironment to support tumor development.

SUBMITTER: Yang C

PROVIDER: S-EPMC4684331 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Protumoral TSP50 Regulates Macrophage Activities and Polarization via Production of TNF-α and IL-1β, and Activation of the NF-κB Signaling Pathway.

Yang Cheng C Zhang Dong-Mei DM Song Zhen-Bo ZB Hou Ya-Qin YQ Bao Yong-Li YL Sun Lu-Guo LG Yu Chun-Lei CL Li Yu-Xin YX

PloS one 20151218 12

Testes-specific protease 50 (TSP50) is abnormally overexpressed in many kinds of cancers and promotes cell proliferation and migration. However, whether TSP50 can influence the tumor microenvironment, especially the function of immune cells in the microenvironment, remains largely unknown. We demonstrated that exposure to the conditioned medium from TSP50-overexpressing cells, or co-culture with TSP50-overexpressing cells, enhanced the cytokine production and phagocytic activities of macrophages ...[more]

PMID: 26684869

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Project description:Baicalein is one of the bioactive compounds extracted from Scutellaria baicalensis. Recent studies indicated the antitumor effects of baicalein, however, the underlying mechanisms are needed to be further determined. In this study, we found that baicalein could inhibit the tumor growth in mice models of breast cancer and melanoma and worked as an immunomodulator to promote the infiltration of tumor-associated macrophages (TAMs) and skew the TAMs towards the M1-like phenotype. Baicalein also induced M1-like phenotype polarization in THP-1-derived macrophages. Meanwhile, the expression of pro-inflammatory factors associated with M1 macrophages, including TNF-α, IL-1β, CXCL9 and CXCL10, were increased after baicalein treatment. Mechanistically, the RNA-seq data suggested that baicalein potentiated the M1 macrophage polarization via the NF-κB/TNF-α signaling pathway. ELISA and confocal microscopy assay confirmed that baicalein significantly induced the production of TNF-α and the activation of NF-κB, while TNF-α neutralization inhibited baicalein-induced macrophage polarization toward M1, and NF-κB P65 knock-down suppressed baicalein-induced TNF-α production in THP-1-derived macrophages. Phosphoinositide 3-kinase (PI3k) γ has been reported as a key molecule in macrophage polarization, and inhibition of PI3Kγ activates the NF-κB-related inflammatory signals. Our pharmacological network analysis predicted that PI3Kγ might be one of the major targets of baicalein. The results from the docking program and surface plasmon resonance (SPR) confirmed that baicalein displayed good binding activity to PI3Kγ. We further found that baicalein not only exhibited a direct inhibitory effect on the protein kinase activity of PI3Kγ, but also reduced the mRNA and protein expression of PI3Kγ, indicating that baicalein might be a novel PI3Kγ inhibitor. In summary, baicalein mediated the TAMs skewing to M1-TAMs, and then retarded tumor growth. These effects, at least in part, were linked to the PI3Kγ/NF-κB signaling.

Dataset Information

Protumoral TSP50 Regulates Macrophage Activities and Polarization via Production of TNF-? and IL-1?, and Activation of the NF-?B Signaling Pathway.

Publications

Protumoral TSP50 Regulates Macrophage Activities and Polarization via Production of TNF-α and IL-1β, and Activation of the NF-κB Signaling Pathway.

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