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ATF4 is directly recruited by TLR4 signaling and positively regulates TLR4-trigged cytokine production in human monocytes

Cellular & Molecular Immunology volume 10, pages 84–94 (2013)Cite this article

Abstract

Toll-like receptors (TLRs) are sentinels of the host defense system, which recognize a large number of microbial pathogens. The host defense system may be inefficient or inflammatory diseases may develop if microbial recognition by TLRs and subsequent TLR-triggered cytokine production are deregulated. Activating transcription factor 4 (ATF4), a member of the ATF/CREB transcription factor family, is an important factor that participates in several pathophysiological processes. In this report, we found that ATF4 is also involved in the TLR-mediated innate immune response, which participates in TLR4 signal transduction and mediates the secretion of a variety of cytokines. We observed that ATF4 is activated and translocates to the nucleus following lipopolysaccharide (LPS) stimulation via the TLR4-MyD88-dependent pathway. Additionally, a cytokine array assay showed that some key inflammatory cytokines, such as IL-6, IL-8 and RANTES, are positively regulated by ATF4. We also demonstrate that c-Jun directly binds to ATF4, thereby promoting the secretion of inflammatory cytokines. Taken together, these results indicate that ATF4 acts as a positive regulator in TLR4-triggered cytokine production.

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Acknowledgements

We thank Dr Feifei Liu and Xiaoyue Tan for kindly reading the manuscript and providing valuable advice. This work was supported by Tianjin Municipal Science and Technology Commission, Grant No. 08ZCGYSH04700.

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  1. Dr Chenghu Liu, The School of Medicine, Nankai University, 94 Weijin Road, Tianjin 300071, China. E-mail: cl45@nankai.edu.cn

  2. Dr Rong Xiang, The School of Medicine, Nankai University, 94 Weijin Road, Tianjin 300071, China. E-mail: rxiang@nankai.edu.cn

Authors and Affiliations

  1. Department of Immunology, Nankai University School of Medicine, Tianjin, China

    Chunyan Zhang, Nan Bai, Antao Chang, Zhuhong Zhang, Jing Yin, Wenzhi Shen, Rong Xiang & Chenghu Liu

  2. Department of Clinical Biochemistry, Chinese PLA General Hospital, Beijing, China

    Chunyan Zhang & Yaping Tian

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Zhang, C., Bai, N., Chang, A. et al. ATF4 is directly recruited by TLR4 signaling and positively regulates TLR4-trigged cytokine production in human monocytes. Cell Mol Immunol 10, 84–94 (2013). https://doi.org/10.1038/cmi.2012.57

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