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

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-?B) 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-?B and JNK by TNF-? 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 I?B? in ATF3-/- MEF cells were substantially higher than those in wild type MEF cells upon microarray analyses, and upregulated I?B? 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 I?B? expression and that the high levels of I?B? expression in ATF3-/- cells disrupts Kdo(2)-Lipid A-mediated signaling pathways.

SUBMITTER: Kim EY

PROVIDER: S-EPMC2996292 | biostudies-other | 2010

REPOSITORIES: biostudies-other

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

Kim Eun-Young EY Shin Hye Young HY Kim Joo-Young JY Kim Dong-Gun DG Choi Yong-Min YM Kwon Hyuk-Kwon HK Rhee Dong-Kwon DK Kim You-Sun YS Choi Sangdun S

PloS one 20101202 12

<h4>Background</h4>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 (J ...[more]

PMID: 21152039

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Project description:Atherosclerosis is a chronic degenerative disease of the arteries and is thought to be one of the most common causes of death globally. In recent years, the functions of adventitial fibroblasts in the development of atherosclerosis and tissue repair have gained increased interests. LPS can increase the morbidity and mortality of atherosclerosis-associated cardiovascular disease. Although LPS increases neointimal via TLR4 activation has been reported, how LPS augments atherogenesis through acting on adventitial fibroblasts is still unknown. Here we explored lipid deposition within adventitial fibroblasts mediated by lipopolysaccharide (LPS) to imitate inflammatory conditions.In our study, LPS enhanced lipid deposition by the up-regulated expression of adipose differentiation-related protein (ADRP) as the silencing of ADRP abrogated lipid deposition in LPS-activated adventitial fibroblasts. In addition, pre-treatment with anti-Toll-like receptor 4 (TLR4) antibody diminished the LPS-induced lipid deposition and ADRP expression. Moreover, LPS induced translocation of nuclear factor-?B (NF-?B), which could markedly up-regulate lipid deposition as pre-treatment with the NF-?B inhibitor, PDTC, significantly reduced lipid droplets. In addition, the lowering lipid accumulation was accompanied with the decreased ADRP expression. Furthermore, LPS-induced adventitial fibroblasts secreted more monocyte chemoattractant protein (MCP-1), compared with transforming growth factor-?1 (TGF-?1).Taken together, these results suggest that LPS promotes lipid accumulation via the up-regulation of ADRP expression through TLR4 activated downstream of NF-?B in adventitial fibroblasts. Increased levels of MCP-1 released from LPS-activated adventitial fibroblasts and lipid accumulation may accelerate monocytes recruitment and lipid-laden macrophage foam cells formation. Here, our study provides a new explanation as to how bacterial infection contributes to the pathological process of atherosclerosis.

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

Publications

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

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