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ATF3 plays a key role in Kdo2-lipid A-induced TLR4-dependent gene expression via NF-κB activation.

Authors
Kim, EY; Shin, HY; Kim, JY; Kim, DG; Choi, YM; Kwon, HK; Rhee, DK; Kim, YS; Choi, S
Citation
PloS one, 5(12):e14181-e14181, 2010
Journal Title
PloS one
ISSN
1932-6203
Abstract
BACKGROUND: Activating transcription factor 3 (ATF3) is a negative regulator of proinflammatory cytokine expression in macrophages, and ATF3 deficient mice are more susceptible to endotoxic shock. This study addresses the role of ATF3 in the Kdo(2)-Lipid A-induced Toll-like receptor 4 (TLR4) signaling pathway in mouse embryonic fibroblasts (MEF). Kdo(2)-Lipid A upregulates ATF3 expression in wild type MEF cells and induces both nuclear factor kappa B (NF-κB) and c-Jun N-terminal kinase (JNK) activation via the TLR4 signaling pathway, while neither of these pathways is activated in ATF3-/- MEF cells. Interestingly, in contrast to Kdo(2)-Lipid A, the activation of both NF-κB and JNK by TNF-α was normal in ATF3-/- MEF cells.



METHODOLOGY/PRINCIPAL FINDINGS: We found that several genes were dramatically upregulated in ATF3+/+ MEF cells in response to Kdo(2)-Lipid A treatment, while little difference was observed in the ATF3-/- MEF cells. However, we also found that the signal intensities of IκBζ in ATF3-/- MEF cells were substantially higher than those in wild type MEF cells upon microarray analyses, and upregulated IκBζ expression was detected in the cytosol fraction.



CONCLUSIONS/SIGNIFICANCE: Our findings indicate that ATF3 deficiency affects Kdo(2)-Lipid A-induced TLR4 signaling pathways in MEF cells, that it may upregulate IκBζ expression and that the high levels of IκBζ expression in ATF3-/- cells disrupts Kdo(2)-Lipid A-mediated signaling pathways.
DOI
10.1371/journal.pone.0014181
PMID
21152039
Appears in Collections:
Journal Papers > School of Medicine / Graduate School of Medicine > Biochemistry & Molecular Biology
AJOU Authors
김, 유선
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