Role of caspase-8 in hepatocyte response to infection and injury in mice

Moshe, Tehila Ben; Barash, Hila; Kang, Tae-Bong; Kim, Jin‐Chul; Kovalenko, Andrew; Gross, Eitan; Schuchmann, Marcus; Abramovitch, Rinat; Galun, Eithan; Wallach, David

doi:10.1002/hep.21495

Cited by 73 publications

(64 citation statements)

References 46 publications

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“…The increase in the CASP8 active fragment may be more related to the non-apoptotic functions of the protease in the liver, such as cell proliferation and induction of inflammation (Ben Moshe et al 2007). Surprisingly, we did not detect a corresponding increase in CASP8 activity in the liver.…”

Section: Caspases Expression and Processing Of Stk3 In The Livercontrasting

confidence: 75%

Organ-specific alteration in caspase expression and STK3 proteolysis during the aging process

Lessard‐Beaudoin

Laroche

Loudghi

et al. 2016

Neurobiology of Aging

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Caspases and their substrates are key mediators of apoptosis and strongly implicated in various physiological processes. As the STK family is involved in apoptosis, and STK3 is a recently identified caspase-6 substrate, we assessed the expression and cleavage of STK3 in murine peripheral organs and brain regions during the aging process. We also assessed caspase-3, -6, -7 and -8 expression and activity in order to delineate potential mechanism(s) underlying the generation of the STK3 fragments observed, and their relation to the apoptotic pathway. We demonstrate for the first time the cleavage of STK3 by caspase-7 and show that STK3 protein levels globally increase throughout the organism with age. In contrast, caspase-3, -6, -7 and -8 expression and activity vary significantly amongst the different organs analyzed suggesting differential effects of aging on the apoptotic mechanism and/or non-apoptotic functions of caspases throughout the organism. These results further our understanding of the role of caspases and their substrates in the normal aging process and highlight a potential role for STK3 in neurodegeneration.3

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Section: Caspases Expression and Processing Of Stk3 In The Livercontrasting

confidence: 75%

Organ-specific alteration in caspase expression and STK3 proteolysis during the aging process

Lessard‐Beaudoin

Laroche

Loudghi

et al. 2016

Neurobiology of Aging

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“…We found, however, that epidermal deficiency of caspase-8 did have a pronounced effect on skin homeostasis in that it gave rise to a chronic inflammatory disease associated with a hyperproliferative state. In a previous study we found that caspase-8 deficiency in hepatocytes promotes chronic inflammation in the liver after partial hepatectomy (Ben Moshe et al, 2007, 2008). The present study shows that widespread inflammation also develops in mice that express an enzymatically inactive caspase-8 allele.…”

Section: Discussionmentioning

confidence: 94%

Caspase-8 deficiency in epidermal keratinocytes triggers an inflammatory skin disease

Kovalenko¹,

Kim²,

Kang³

et al. 2009

J Cell Biol

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Expression of enzymatically inactive caspase-8, or deletion of caspase-8 from basal epidermal keratinocytes, triggers chronic skin inflammation in mice. Unlike similar inflammation resulting from arrest of nuclear factor B activation in the epidermal cells, the effect induced by caspase-8 deficiency did not depend on TNF, IL-1, dermal macrophage function, or expression of the toll-like receptor adapter proteins MyD88 or TRIF. Both interferon regulatory factor (IRF) 3 and TANK-binding kinase were constitutively phosphorylated in the caspase-8-deficient epidermis, and knockdown of IRF3 in the epidermis-derived cells from these mice abolished the expression of up-regulated genes. Temporal and spatial analyses of the alterations in gene expression that result from caspase-8 deficiency reveal that the changes are initiated before birth, around the time that cornification develops, and occur mainly in the suprabasal layer. Finally, we found that caspase-8-deficient keratinocytes display an enhanced response to gene activation by transfected DNA. Our findings suggest that an enhanced response to endogenous activators of IRF3 in the epidermis, presumably generated in association with keratinocyte differentiation, contributes to the skin inflammatory process triggered by caspase-8 deficiency.

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“…Previous studies have also reported an inflammasome-independent role for caspase-8 in inhibiting extensive inflammation in vivo. 72,73 Conditional deletion of caspase-8 in hepatocytes, augments Listeria infection in liver and chronic inflammation following hepatectomy. 73 Caspase-8 deficiency also protects against inflammation-related hepatocarcinogenesis, while inducing Although Ub-RIP1 can enhance the phosphorylation of IRF3, it is also cleaved by activated caspase-8.…”

Section: Caspases In Inflammation and Immunitymentioning

confidence: 99%

“…72,73 Conditional deletion of caspase-8 in hepatocytes, augments Listeria infection in liver and chronic inflammation following hepatectomy. 73 Caspase-8 deficiency also protects against inflammation-related hepatocarcinogenesis, while inducing Although Ub-RIP1 can enhance the phosphorylation of IRF3, it is also cleaved by activated caspase-8. Cleaved RIP1 inhibits IRF3 and NFκB thereby reducing the type I interferon (IFN) and IL-1β-/IL-18-mediated inflammatory responses.…”

Section: Caspases In Inflammation and Immunitymentioning

confidence: 99%

Old, new and emerging functions of caspases

et al. 2014

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Caspases are proteases with a well-defined role in apoptosis. However, increasing evidence indicates multiple functions of caspases outside apoptosis. Caspase-1 and caspase-11 have roles in inflammation and mediating inflammatory cell death by pyroptosis. Similarly, caspase-8 has dual role in cell death, mediating both receptor-mediated apoptosis and in its absence, necroptosis. Caspase-8 also functions in maintenance and homeostasis of the adult T-cell population. Caspase-3 has important roles in tissue differentiation, regeneration and neural development in ways that are distinct and do not involve any apoptotic activity. Several other caspases have demonstrated anti-tumor roles. Notable among them are caspase-2, -8 and -14. However, increased caspase-2 and -8 expression in certain types of tumor has also been linked to promoting tumorigenesis. Increased levels of caspase-3 in tumor cells causes apoptosis and secretion of paracrine factors that promotes compensatory proliferation in surrounding normal tissues, tumor cell repopulation and presents a barrier for effective therapeutic strategies. Besides this caspase-2 has emerged as a unique caspase with potential roles in maintaining genomic stability, metabolism, autophagy and aging. The present review focuses on some of these less studied and emerging functions of mammalian caspases.

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Role of caspase-8 in hepatocyte response to infection and injury in mice

Cited by 73 publications

References 46 publications

Organ-specific alteration in caspase expression and STK3 proteolysis during the aging process

Organ-specific alteration in caspase expression and STK3 proteolysis during the aging process

Caspase-8 deficiency in epidermal keratinocytes triggers an inflammatory skin disease

Old, new and emerging functions of caspases

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