TNF-α induces CXCL1 chemokine expression and release in human vascular endothelial cells in vitro via two distinct signaling pathways

Lo, Huey‐Ming; Lai, Tsung‐Ching; Li, Chih-hung; Wu, Wen‐Bin

doi:10.1038/aps.2013.182

Cited by 70 publications

(61 citation statements)

References 30 publications

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“…6b), suggesting that lack of presenilins affects TNF␣-mediated CXCL1 chemokine production. Interestingly, and consistent with our reported defect in JNK MAPK activation in PS DKO MEFs, it has been reported that CXCL1 production is dependent upon TNF␣-stimulated JNK MAPK activation (72)(73)(74). To further validate this observation, we used wild type and the partial knock-out Psen1 ϩ/Ϫ / Psen2 Ϫ/Ϫ murine model, which have the maximum reduction in presenilin expression that is compatible with viability.…”

Section: Presenilin Deficiency Is Associated With Enhanced Formation supporting

confidence: 77%

γ-Secretase Activity Is Required for Regulated Intramembrane Proteolysis of Tumor Necrosis Factor (TNF) Receptor 1 and TNF-mediated Pro-apoptotic Signaling

Chhibber‐Goel

Coleman-Vaughan

Agrawal

et al. 2016

Journal of Biological Chemistry

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The ␥-secretase protease and associated regulated intramembrane proteolysis play an important role in controlling receptormediated intracellular signaling events, which have a central role in Alzheimer disease, cancer progression, and immune surveillance. An increasing number of ␥-secretase substrates have a role in cytokine signaling, including the IL-6 receptor, IL-1 receptor type I, and IL-1 receptor type II. In this study, we show that following TNF-converting enzyme-mediated ectodomain shedding of TNF type I receptor (TNFR1), the membranebound TNFR1 C-terminal fragment is subsequently cleaved by ␥-secretase to generate a cytosolic TNFR1 intracellular domain. We also show that clathrin-mediated internalization of TNFR1 C-terminal fragment is a prerequisite for efficient ␥-secretase cleavage of TNFR1. Furthermore, using in vitro and in vivo model systems, we show that in the absence of presenilin expression and ␥-secretase activity, TNF-mediated JNK activation was prevented, assembly of the TNFR1 pro-apoptotic complex II was reduced, and TNF-induced apoptosis was inhibited. These observations demonstrate that TNFR1 is a ␥-secretase substrate and suggest that ␥-secretase cleavage of TNFR1 represents a new layer of regulation that links the presenilins and the ␥-secretase protease to pro-inflammatory cytokine signaling.The biological activities of the tumor necrosis factor-␣ (TNF) pro-inflammatory cytokine are resolved by two distinct cell surface receptors, TNFR1 3 and TNFR2, which elicit a diversity of cellular responses, such as inflammation, cell proliferation, cell differentiation, and initiation of apoptosis (1-10). TNFR1 initiates either pro-inflammatory or pro-apoptotic signaling through the selective recruitment of intracellular adaptor and effector proteins (1,3,6,7,11). Ligand binding and trimerization of TNFR1 enables the recruitment of TNFR1-associated death domain protein (TRADD) (12, 13), which functions as a scaffold enabling the recruitment of receptorinteracting protein kinase 1 (RIPK1) (14 -16), TNF receptorassociated factor 2 (TRAF2) or TRAF5 (12), and the cellular inhibitor of apoptosis proteins (cIAPs) cIAP1 and cIAP2 (11), which collectively form a signaling composite called complex I (17-19). The resulting lysine 63-linked polyubiquitination of RIPK1 by TRAF2 and the cIAPs (20 -24) enables an interaction with the IB kinase complex that mediates the phosphorylation and degradation of IB-inhibitory proteins and activation of the transcription factor NF-B to promote non-apoptotic signaling pathways (25-27). NF-B also increases expression of anti-apoptotic genes, including cIAPs and FLICE inhibitory protein (c-FLIP), further ensuring a non-apoptotic signaling pathway.The importance of receptor internalization as a regulatory mechanism for the segregation and divergence of intracellular signaling pathways is highlighted by studies on internalization of TNFR1 and TNFR2, the Fas receptor (FasR/CD95), IL-1 receptor I, Toll-like receptor 4, and TRAIL receptors (18, 28 -33). The current favored m...

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Section: Presenilin Deficiency Is Associated With Enhanced Formation supporting

confidence: 77%

γ-Secretase Activity Is Required for Regulated Intramembrane Proteolysis of Tumor Necrosis Factor (TNF) Receptor 1 and TNF-mediated Pro-apoptotic Signaling

Chhibber‐Goel

Coleman-Vaughan

Agrawal

et al. 2016

Journal of Biological Chemistry

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“…4A and B. We observed that SB202190 did not affect p38 MAPK phosphorylation, even though its specificity and inhibitory ability on p38 MAPK have been demonstrated by us and others [23,24]. Under these conditions, we observed that both JNK and p38 MAPK inhibitors markedly inhibited TNF-α-induced Akt activation and slightly affected PI-3K activation.…”

Section: Resultssupporting

confidence: 62%

“…3). In this regard, the regulatory mechanism by TNF-α in A549 cells is similar to that observed in human umbilical vein endothelial cells (HUVECs) treated with TNF-α [24]. However, there are also some differences between these two cell types in response to TNF-α and other stimulators, revealing an interesting cell type-specific feature.…”

Section: Discussionmentioning

confidence: 58%

“…However, there are also some differences between these two cell types in response to TNF-α and other stimulators, revealing an interesting cell type-specific feature. First, VEGF and TNF-α are the most potent stimulators of A549 epithelial cells, whereas LPS and TNF-α are stimulators of HUVECs [19,24]. Second, the steroid dexamethasone markedly inhibited TNF-α-induced CXCL1 release by A549 epithelial cells, though it failed to affect CXCL1 release by HUVECs (Fig.…”

Section: Discussionmentioning

confidence: 99%

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CXCL1 Regulation in Human Pulmonary Epithelial Cells by Tumor Necrosis Factor

Shieh

Tsou

2014

Cell Physiol Biochem

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Background/Aims: The chemokine CXCL1 has been reported to be expressed in lung airway epithelium and non-small cell lung cancer biopsy specimens. In this study, we investigated the effects of TNF-α, an abundant cytokine detected in inflammation and various cancers, on CXCL1 release by human A549 lung carcinoma epithelial cells. Methods: CXCL1 expression was determined by ELISA and RT-PCR. TNF-α signaling was examined by western blotting. Monocyte migration was assayed by a Transwell migration system. Results: TNF-α stimulated CXCL1 release and mRNA expression, and this release was inhibited by inhibitors of JNK, p38 MAPK, PI-3K/Akt and AP-1 transcription factor. TNF-α treatment was followed by JNK, p38 MAPK and PI3K/Akt activation. However, only the JNK inhibitor could reduce the CXCL1 mRNA level, suggesting that JNK is required mainly for CXCL1 mRNA synthesis, whereas p38 MAPK and PI-3K/Akt might be responsible for CXCL1 secretion. Dexamethasone (dex) and TGF-β reduced CXCL1 secretion, with dex upregulating the expression of MAP kinase phosphatase-1 and TGF-β causing smad2/3 activation and nuclear translocation. A functional analysis showed that the released CXCL1 enhanced monocyte migration and could be abolished by a CXCL1 neutralizing antibody and CXCR antagonist. Conclusion: We demonstrate that TNF-α induces CXCL1 expression through the JNK, p38 MAPK and PI-3K/Akt signaling pathways in human pulmonary epithelial cells.

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“…The ECs were prepared and characterized by a previously described method. 23,24 Isolated ECs were maintained in M199 containing 20% fetal bovine serum, 30 µg/mL endothelial cell growth supplement, 4 mM L-glutamine, 100 U/mL penicillin, 100 µg/mL streptomycin, and 250 ng/mL Fungizone (Thermo Fisher Scientific). The cells were used between the second and fourth passages in this study.…”

Section: Cell Culturesmentioning

confidence: 99%

Gold nanoparticles induce heme oxygenase-1 expression through Nrf2 activation and Bach1 export in human vascular endothelial cells

Lai¹,

Shieh²,

Tsou³

et al. 2015

IJN

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It has been reported that increased levels and activity of the heme oxygenase-1 (HO-1) protein ameliorate tissue injuries. In the present study, we investigated the effects and mechanisms of action of gold nanoparticles (AuNPs) on HO-1 protein expression in human vascular endothelial cells (ECs). The AuNPs induced HO-1 protein and mRNA expression in a concentration- and time-dependent manner. The induction was reduced by the thiol-containing antioxidants, including N-acetylcysteine and glutathione, but not by the non-thiol-containing antioxidants and inhibitors that block the enzymes for intracellular reactive oxygen species generation. The AuNPs enhanced Nrf2 protein levels but did not affect Nrf2 mRNA expression. In response to the AuNP treatment, the cytosolic Nrf2 translocated to the nucleus, and, concomitantly, Bach1 exited the nucleus and its tyrosine phosphorylation increased. The chromatin immunoprecipitation assay revealed that the translocated Nrf2 bound to the antioxidant-response element located in the E2 enhancer region of the HO-1 gene promoter and acted as a transcription factor. Although N-acetylcysteine inhibited the AuNP-induced Nrf2 nuclear translocation, the AuNPs did not promote intracellular reactive oxygen species production or endoplasmic reticulum stress in the ECs. Knockdown of Nrf2 expression by RNA interference significantly inhibited AuNP-induced HO-1 expression at the protein and mRNA levels. In summary, AuNPs enhance the levels and nuclear translocation of the Nrf2 protein and Bach1 export/tyrosine phosphorylation, leading to Nrf2 binding to the HO-1 E2 enhancer promoter region to drive HO-1 expression in ECs. This study, together with our parallel findings, demonstrates that AuNPs can act as an HO-1 inducer, which may partially contribute to their anti-inflammatory bioactivity in human vascular ECs.

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TNF-α induces CXCL1 chemokine expression and release in human vascular endothelial cells in vitro via two distinct signaling pathways

Abstract: TNF-α stimulates CXCL1 release from human ECs through JNK-mediated CXCL1 mRNA expression and p38 MAPK- and PI-3K-mediated CXCL1 secretory processes.

Cited by 70 publications

References 30 publications

γ-Secretase Activity Is Required for Regulated Intramembrane Proteolysis of Tumor Necrosis Factor (TNF) Receptor 1 and TNF-mediated Pro-apoptotic Signaling

γ-Secretase Activity Is Required for Regulated Intramembrane Proteolysis of Tumor Necrosis Factor (TNF) Receptor 1 and TNF-mediated Pro-apoptotic Signaling

CXCL1 Regulation in Human Pulmonary Epithelial Cells by Tumor Necrosis Factor

Gold nanoparticles induce heme oxygenase-1 expression through Nrf2 activation and Bach1 export in human vascular endothelial cells

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