Journal
CELLULAR & MOLECULAR IMMUNOLOGY
Volume 10, Issue 1, Pages 84-94Publisher
CHIN SOCIETY IMMUNOLOGY
DOI: 10.1038/cmi.2012.57
Keywords
ATF4; cytokine; MyD88; TLR4 signaling pathway; TRIF
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Funding
- Tianjin Municipal Science and Technology Commission [08ZCGYSH04700]
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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. Cellular & Molecular Immunology (2013) 10, 84-94; doi:10.1038/cmi.2012.57; published online 17 December 2012
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