The Role of Apoptosis Signal-regulating Kinase 1 in Lymphotoxin-β Receptor-mediated Cell Death

Chen, Mei Chieh; Hwang, Ming Jing; Chou, Yang Chieh; Chen, Wei Hsu; Cheng, Genhong; Nakano, Hiroyasu; Luh, Tien‐Yau; Chih, Shen; Hsieh, Shie Liang

doi:10.1074/jbc.m208661200

Cited by 54 publications

(66 citation statements)

References 47 publications

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“…In addition, the association of proapoptotic molecules like Smac and IAP-1, along with TRAF-2 and TRAF-3, with the endogenous LIGHT-LTβR complex has been reported (41). More specifically, in a hepatoma cell line, Hep3B, it has been postulated that LIGHT mediates cell death via activation of ROS and Ask-1 downstream of the TRAF-3 and TRAF-5 signals from the LTβR (42). At present, we have not explored whether these mechanisms are responsible for the death of hepatocytes in our hepatitis model, but it is likely that these molecular events play a synergistic role in the hepatocyte cell death.…”

Section: Discussionmentioning

confidence: 99%

Essential role of TNF family molecule LIGHT as a cytokine in the pathogenesis of hepatitis

Anand

Wang

Yoshimura

et al. 2006

Journal of Clinical Investigation

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LIGHT is an important costimulatory molecule for T cell immunity. Recent studies have further implicated its role in innate immunity and inflammatory diseases, but its cellular and molecular mechanisms remain elusive. We report here that LIGHT is upregulated and functions as a proinflammatory cytokine in 2 independent experimental hepatitis models, induced by concanavalin A and Listeria monocytogenes. Molecular mutagenesis studies suggest that soluble LIGHT protein produced by cleavage from the cell membrane plays an important role in this effect through the interaction with the lymphotoxin-β receptor (LTβR) but not herpes virus entry mediator. NK1.1 + T cells contribute to the production, but not the cleavage or effector functions, of soluble LIGHT. Importantly, treatment with a mAb that specifically interferes with the LIGHT-LTβR interaction protects mice from lethal hepatitis. Our studies thus identify a what we believe to be a novel function of soluble LIGHT in vivo and offer a potential target for therapeutic interventions in hepatic inflammatory diseases.

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Section: Discussionmentioning

confidence: 99%

Essential role of TNF family molecule LIGHT as a cytokine in the pathogenesis of hepatitis

Anand

Wang

Yoshimura

et al. 2006

Journal of Clinical Investigation

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“…The HA-tagged expression constructs for catalytically inactive ASK1-K709E [ASK1 dominant-negative mutant (DN)] and pcDNA were derived as described previously (Chen et al, 2003). MKK3 DN, MKK6 DN, and p38MAPK DN were kindly provided by Dr. C. M. Teng (National Taiwan University, Taipei, Taiwan).…”

Section: Methodsmentioning

confidence: 99%

Apoptosis Signal-Regulating Kinase 1 in Amyloid β Peptide-Induced Cerebral Endothelial Cell Apoptosis

Hsu¹,

Hsu²,

Chen³

et al. 2007

J. Neurosci.

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A pathological hallmark of Alzheimer's disease is accumulation of amyloid-␤ peptide (A␤) in senile plaques. A␤ has also been implicated in vascular degeneration in cerebral amyloid angiopathy because of its cytotoxic effects on non-neuronal cells, including cerebral endothelial cells (CECs). We explore the role of apoptosis signal-regulating kinase 1 (ASK1) in A␤-induced death in primary cultures of murine CECs. A␤ induced ASK1 dephosphorylation, which could be prevented by selective inhibition of protein phosphatase 2A (PP2A) but not PP2B. ASK1 dephosphorylation resulted in its dissociation from 14-3-3. ASK1, released from 14-3-3 inhibition, activated p38 mitogen-activated protein kinase (p38MAPK), leading to p53 phosphorylation. p53, a proapoptotic transcription factor, in turn transactivated the expression of Bax, a proapoptotic protein. Transfection with various dominant-negative mutants (DNs), including ASK1 DN and p38MAPK DN, suppressed A␤-induced p38MAPK activation, p53 phosphorylation, and Bax upregulation and partially prevented CEC death. Bax knockdown using a bax small interfering RNA strategy also reduced Bax expression and subsequent CEC death. These results suggest that A␤ activates the ASK1-p38MAPK-p53-Bax cascade to cause CEC death in a PP2A-dependent manner.

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“…In addition to the classical and noncanonical NF-B pathways, LT␤R ligation also activates the JNK signaling pathway and induces the transcription factor AP-1 in some cell types (35). As this pathway has not been examined in EC following LT␤R ligation, we explored JNK signaling in HUVEC by immunoblotting for c-jun and phosphorylated c-jun.…”

Section: Light and Lt␣1␤2 But Not Tnf Induce P100 Processing To P52mentioning

confidence: 99%

Lymphotoxin-α1β2 and LIGHT Induce Classical and Noncanonical NF-κB-Dependent Proinflammatory Gene Expression in Vascular Endothelial Cells

Madge

Kluger

Orange

et al. 2008

The Journal of Immunology

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Activation of the classical and noncanonical NF-κB pathways by ligation of the lymphotoxin (LT)-β receptor (LTβR) plays a crucial role in lymphoid organogenesis and in the generation of ectopic lymphoid tissue at sites of chronic inflammation. Within these microenvironments, LTβR signaling regulates the phenotype of the specialized high endothelial cells. However, the direct effects of LTβR ligation on endothelial cells remain unclear. We therefore questioned whether LTβR ligation could directly activate endothelial cells and regulate classical and noncanonical NF-κB-dependent gene expression. We demonstrate that the LTβR ligands LIGHT and LTα1β2 activate both NF-κB pathways in HUVECs and human dermal microvascular endothelial cells (HDMEC). Classical pathway activation was less robust than TNF-induced signaling; however, only LIGHT and LTα1β2 and not TNF activated the noncanonical pathway. LIGHT and LTα1β2 induced the expression of classical NF-κB-dependent genes in HUVEC, including those encoding the adhesion molecules E-selectin, ICAM-1, and VCAM-1. Consistent with this stimulation, LTβR ligation up-regulated T cell adhesion to HUVEC. Furthermore, the homeostatic chemokine CXCL12 was up-regulated by LIGHT and LTα1β2 but not TNF in both HUVEC and HDMEC. Using HUVEC retrovirally transduced with dominant negative IκB kinase α, we demonstrate that CXCL12 expression is regulated by the noncanonical pathway in endothelial cells. Our findings therefore demonstrate that LTβR ligation regulates gene expression in endothelial cells via both NF-κB pathways and we identify CXCL12 as a bona fide noncanonical NF-κB-regulated gene in these cells.

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The Role of Apoptosis Signal-regulating Kinase 1 in Lymphotoxin-β Receptor-mediated Cell Death

Cited by 54 publications

References 47 publications

Essential role of TNF family molecule LIGHT as a cytokine in the pathogenesis of hepatitis

Essential role of TNF family molecule LIGHT as a cytokine in the pathogenesis of hepatitis

Apoptosis Signal-Regulating Kinase 1 in Amyloid β Peptide-Induced Cerebral Endothelial Cell Apoptosis

Lymphotoxin-α1β2 and LIGHT Induce Classical and Noncanonical NF-κB-Dependent Proinflammatory Gene Expression in Vascular Endothelial Cells

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