title: ATF4 is directly recruited by TLR4 signaling and positively regulates TLR4-trigged cytokine production in human monocytes.
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.
authors.affiliation: Department of Immunology, Nankai University School of Medicine, Tianjin, China.
authors.forename: Chunyan
authors.initials: C
authors.lastname: Zhang
authors.forename: Nan
authors.initials: N
authors.lastname: Bai
authors.forename: Antao
authors.initials: A
authors.lastname: Chang
authors.forename: Zhuhong
authors.initials: Z
authors.lastname: Zhang
authors.forename: Jing
authors.initials: J
authors.lastname: Yin
authors.forename: Wenzhi
authors.initials: W
authors.lastname: Shen
authors.forename: Yaping
authors.initials: Y
authors.lastname: Tian
authors.forename: Rong
authors.initials: R
authors.lastname: Xiang
authors.forename: Chenghu
authors.initials: C
authors.lastname: Liu
mesh_terms: D051701:Activating Transcription Factor 4 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D021581:Active Transport, Cell Nucleus / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D002467:Cell Nucleus / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D016207:Cytokines / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects / Q000235:genetics; D008070:Lipopolysaccharides / Q000494:pharmacology; D009000:Monocytes / Q000276:immunology* / Q000378:metabolism; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics / Q000276:immunology*; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D020298:U937 Cells
chemical_list: C497109:ATF4 protein, human; D016207:Cytokines; D008070:Lipopolysaccharides; D016755:Proto-Oncogene Proteins c-jun; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D051701:Activating Transcription Factor 4