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ATF3 plays a key role in Kdo2-lipid A-induced TLR4-dependent gene expression via NF-κB activation.
- Source :
- PLoS ONE, Vol 5, Iss 12, p e14181 (2010)
- Publication Year :
- 2010
- Publisher :
- Public Library of Science (PLoS), 2010.
-
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.
Details
- Language :
- English
- ISSN :
- 19326203
- Volume :
- 5
- Issue :
- 12
- Database :
- Directory of Open Access Journals
- Journal :
- PLoS ONE
- Publication Type :
- Academic Journal
- Accession number :
- edsdoj.bacf248ea81a491a90b4680d0b018ff1
- Document Type :
- article
- Full Text :
- https://doi.org/10.1371/journal.pone.0014181