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Cripto-1 modulates macrophage cytokine secretion and phagocytic activity via NF-κB signaling

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Abstract

Cripto-1 is an oncogenic protein belonging to the epidermal growth factor–Cripto-1/FRL-1/Cryptic family. It has important roles in tumor formation and metastasis, but its effects on the immune system are unclear. In the present study, we investigated the effects of Cripto-1 overexpression on macrophage activities and examined the underlying mechanisms. A cell line stably overexpressing Cripto-1 was developed. The culture supernatant from this cell line was collected and used to condition macrophages (RAW264.7, THP-1, and primary mouse macrophages) for various times. Exposure to this supernatant significantly increased the mRNA and protein expression levels of the anti-inflammatory cytokine interleukin (IL)-10 and of three pro-inflammatory cytokines (tumor necrosis factor-α, IL-6, and IL-1β), but did not affect the expression of transforming growth factor-β, another anti-inflammatory cytokine. Exposure to this supernatant also enhanced macrophage phagocytosis of chicken erythrocytes and yeast cells. Similar effects were observed in macrophages stimulated with purified Cripto-1 protein. Mechanistic experiments revealed that Cripto-1 activated nuclear factor (NF)-κB signaling by inducing IκB kinase phosphorylation and p65 nuclear translocation. Pretreatment with ammonium pyrrolidine dithiocarbamate, a specific NF-κB inhibitor, inhibited Cripto-1-induced cytokine secretion and phagocytosis of macrophages. Taken together, our present findings suggest that Cripto-1 enhances macrophage phagocytic activity and upregulates the production of anti- and pro-inflammatory cytokines via the NF-κB signaling pathway.

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Acknowledgments

This work was supported by the National High Technology Research and Development Program of China (No. 2012AA02A407), the National Natural Science Foundation of China (Grant Number 30670220), the Fundamental Research Funds for the Central Universities and the Research Foundation of JiLin Provincial Science & Technology Development (Grant No. 20150101188JC). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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Authors and Affiliations

  1. National Engineering Laboratory for Druggable Gene and Protein Screening, Northeast Normal University, Changchun, 130024, China

    Dong-mei Zhang, Yong-Li Bao & Yi-meng Wang

  2. Research Center of Agriculture and Medicine Gene Engineering of Ministry of Education, Northeast Normal University, Changchun, 130024, China

    Dong-mei Zhang

  3. Institute of Genetics and Cytology, Northeast Normal University, Changchun, 130024, China

    Chun-Lei Yu & Zhen-Bo Song

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  1. Dong-mei Zhang
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  2. Yong-Li Bao
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Correspondence to Yong-Li Bao.

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Zhang, Dm., Bao, YL., Yu, CL. et al. Cripto-1 modulates macrophage cytokine secretion and phagocytic activity via NF-κB signaling. Immunol Res 64, 104–114 (2016). https://doi.org/10.1007/s12026-015-8724-3

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  • DOI: https://doi.org/10.1007/s12026-015-8724-3

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