Lymphotoxin α induces apoptosis, necroptosis and inflammatory signals with the same potency as tumour necrosis factor

Etemadi, Nima; Holien, Jessica K.; Chau, Diep; Dewson, Grant; Murphy, James M.; Alexander, Warren S.; Parker, Michael W.; Silke, John; Nachbur, Ueli

doi:10.1111/febs.12419

Cited by 60 publications

(59 citation statements)

References 84 publications

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“…Among the genes that were mostly upregulated by AGE-BSA, we found several genes whose product is a potent inducer of apoptosis, such as Lta (lymphotoxin alphaZ TNFb; Etemadi et al 2013), Tnfsf10 (TRAIL; Falschlehner et al 2007), and Tnf (Table 1). In addition, the expression of other ligands (CD40), receptors (Tnfrsf1b (TNFR2)), and intracellular adaptor proteins (Traf1) involved in apoptotic signaling were upregulated.…”

Section: Resultsmentioning

confidence: 99%

“…Navarro & Mora-Fernández (2006), Roszer (2011) and Xu et al (2013)). In addition to TNFa, AGE-BSA increased the mRNA levels of other apoptogenic ligands, such as lymphotoxin alpha (Etemadi et al 2013) and TRAIL (Falschlehner et al 2007). AGE-BSA also increased the expression of CD40, which was reported to mediate the release of TNFa in osteoblasts (Die et al 2012) as well as induce the apoptosis of carcinoma cells via the production of TNFa and TRAIL (Eliopoulos et al 2000) and that of biliary epithelial cells via the expression of FasL (Afford et al 2001).…”

Section: Discussionmentioning

confidence: 99%

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AGEs induce caspase-mediated apoptosis of rat BMSCs via TNFα production and oxidative stress

Weinberg¹,

Maymon²,

Weinreb³

2013

Journal of Molecular Endocrinology

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Diabetic humans and animals exhibit lower bone mass and healing, resulting from diminished bone formation. We have recently reported that type 1 diabetic rats have fewer bone marrow osteoprogenitor cells, and since the formation of advanced glycation end products (AGEs) in bone increases in diabetes, we explored possible mechanisms involved in AGE-induced apoptosis of rat bone marrow stromal cells (BMSCs). BMSCs isolated from 4-month-old rats were exposed to 10-400 mg/ml AGE-BSA for 16 h and apoptosis was quantified with PI/annexin V staining and flow cytometry. Signaling mechanisms were evaluated by preincubating the cells with appropriate inhibitors. The formation of reactive oxygen species (ROS) was quantified by flow cytometric analysis of DCFDA fluorescence and the expression of genes by RT-PCR analysis. AGE-BSA at a concentration of 400 mg/ml increased the apoptosis of BMSCs two-to threefold, an effect completely blocked by a pan-caspase inhibitor. BSA or high concentrations of glucose had no effect. AGE-BSA-induced BMSC apoptosis was attenuated by a p38 inhibitor but not by an NF-kB inhibitor. Treatment with AGE-BSA induced the expression of several pro-apoptotic ligands and receptors, most notably tumor necrosis factor a (TNFa), TRAIL, lymphotoxin alpha, CD40, and TNFR2. Furthermore, AGE-BSA-induced apoptosis was completely blocked by pirfenidone, an inhibitor of TNFa production/secretion. Finally, AGE-BSA increased the production of ROS in BMSCs, and its apoptogenic effect was blocked by the antioxidant N-acetylcysteine (N-acetyl-L-cysteine). Thus, AGE-BSA increases the apoptosis of rat BMSCs via the activation of caspases, involving TNFa production/ secretion, p38 MAPK signaling, and oxidative stress. We propose that increased protein glycation, such as that occurring under hyperglycemia, causes the apoptosis of BMSCs, which might significantly contribute to the development of osteopenia in diabetic animals.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

AGEs induce caspase-mediated apoptosis of rat BMSCs via TNFα production and oxidative stress

Weinberg¹,

Maymon²,

Weinreb³

2013

Journal of Molecular Endocrinology

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“…33 Caspase 8 À / À /Mlkl À / À and caspase 8 À / À /Ripk3 À / À MDFs were generated as previously described. 47 Antibodies and chemicals. Primary antibodies used for western blot analysis were anti-FLAG (F-3165 Recombinant protein expression and purification.…”

Section: Methodsmentioning

confidence: 99%

RIPK1- and RIPK3-induced cell death mode is determined by target availability

et al. 2014

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Both receptor-interacting protein kinase 1 (RIPK1) and RIPK3 can signal cell death following death receptor ligation. To study the requirements for RIPK-triggered cell death in the absence of death receptor signaling, we engineered inducible versions of RIPK1 and RIPK3 that can be activated by dimerization with the antibiotic coumermycin. In the absence of TNF or other death ligands, expression and dimerization of RIPK1 was sufficient to cause cell death by caspase-or RIPK3-dependent mechanisms. Dimerized RIPK3 induced cell death by an MLKL-dependent mechanism but, surprisingly, also induced death mediated by FADD, caspase 8 and RIPK1. Catalytically active RIPK3 kinase domains were essential for MLKL-dependent but not for caspase 8-dependent death. When RIPK1 or RIPK3 proteins were dimerized, the mode of cell death was determined by the availability of downstream molecules such as FADD, caspase 8 and MLKL. These observations imply that rather than a 'switch' operating between the two modes of cell death, the final mechanism depends on levels of the respective signaling and effector proteins. Mammalian cells can use a number of mechanisms to kill themselves. The best characterized depends on the Bcl-2 family members Bax and Bak that work via mitochondria to activate caspases. 1 Some caspases, notably caspase 8, can be activated independently of Bcl-2 family members, for example, after stimulation of members of the TNF receptor superfamily. 2 Recently, it has become apparent that some of these receptors, including TNFR1, can activate a third suicide mechanism that does not require caspases, and in which the morphology of the dying cell differs from classical apoptosis. This form of cell death, termed 'necroptosis', can often be blocked by necrostatin-1 (nec-1), an inhibitor of the kinase activity of receptor-interacting protein kinase 1 (RIPK1). 3,4 Accordingly, observations from several groups have shown that in some cell types, expression of RIPK1 can signal cell death by caspase-independent necroptosis. 5 It has previously been revealed that RIPK1 could function downstream of death receptors, but in those cases, cell death was usually blocked by coexpression of the viral inhibitor of caspases 1 and 8, CrmA, 6 and typically exhibited a classical 'apoptotic' morphology. It was revealed that RIPK1 engages FADD via homotypic binding of their death domains (DDs), and FADD in turn activates caspase 8. 6,7 RIPK3, like RIPK1, bears a kinase domain and RIP homology interaction motif (RHIM), but unlike RIPK1 does not have a DD. 8-11 RIPK3 is required for necroptosis. 12,13 Furthermore, RIPK1 appears to activate RIPK3 in this pathway, as cell death could be blocked by nec-1. 14 RIPK3 activates, by phosphorylation, MLKL, a pseudokinase essential for this death pathway. [15][16][17] Once activated, MLKL forms multimers that trigger breaches of the plasma membrane. [18][19][20] Although RIPK3 is necessary for necroptosis, it is unclear whether activation of RIPK3 is sufficient for cell death, because TNF activates signaling ...

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“…Even though both TNFα and LTα bind signal via TNFR1, LTα was found to possess less ability to induce TNRF-mediated cell death in an early study [128]. However, a recent research by Etemadi et al displayed that LTα has same potential to induce apoptosis via TNFR1 signaling [129].…”

Section: Tnf and Tnf Receptor 1-2 (Tnfr1 And Tnfr2)mentioning

confidence: 99%

Major apoptotic mechanisms and genes involved in apoptosis

et al. 2016

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As much as the cellular viability is important for the living organisms, the elimination of unnecessary or damaged cells has the opposite necessity for the maintenance of homeostasis in tissues, organs and the whole organism. Apoptosis, a type of cell death mechanism, is controlled by the interactions between several molecules and responsible for the elimination of unwanted cells from the body. Apoptosis can be triggered by intrinsically or extrinsically through death signals from the outside of the cell. Any abnormality in apoptosis process can cause various types of diseases from cancer to auto-immune diseases. Different gene families such as caspases, inhibitor of apoptosis proteins, B cell lymphoma (Bcl)-2 family of genes, tumor necrosis factor (TNF) receptor gene superfamily, or p53 gene are involved and/or collaborate in the process of apoptosis. In this review, we discuss the basic features of apoptosis and have focused on the gene families playing critical roles, activation/inactivation mechanisms, upstream/downstream effectors, and signaling pathways in apoptosis on the basis of cancer studies. In addition, novel apoptotic players such as miRNAs and sphingolipid family members in various kind of cancer are discussed.

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Lymphotoxin α induces apoptosis, necroptosis and inflammatory signals with the same potency as tumour necrosis factor

Cited by 60 publications

References 84 publications

AGEs induce caspase-mediated apoptosis of rat BMSCs via TNFα production and oxidative stress

AGEs induce caspase-mediated apoptosis of rat BMSCs via TNFα production and oxidative stress

RIPK1- and RIPK3-induced cell death mode is determined by target availability

Major apoptotic mechanisms and genes involved in apoptosis

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