Targeted mutation in the Fas gene causes hyperplasia in peripheral lymphoid organs and liver

Adachi, Masashi; Suematsu, Sachiko; Kondo, Toru; Ogasawara, Jun; Tanaka, Takashi; Yoshida, Nobuaki; Nagata, Shinji

doi:10.1038/ng1195-294

Cited by 356 publications

(222 citation statements)

References 48 publications

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“…Humans with Fas mutations present with lymphoproliferation, peripheral expansion of CD4-CD8-αβ-cells and impaired lymphocyte apoptosis in a disorder known as autoimmune lymphoproliferative syndrome (ALPS) (Rieux-Laucat et al, 2003;Sneller et al, 2003). These findings are consistent with observations made in mouse models where CD95 is mutated spontaneously in the lpr mutation (Altman, 1994), or by gene targeted mutations (Adachi et al, 1995;Adachi et al, 1996). In the lpr mutation, a transposable insertion sequence is inserted into the second intron of CD95 resulting in aberrant mRNA transcript splicing and consequently, translation of a truncated protein (Adachi et al, 1993).…”

Section: Introductionsupporting

confidence: 82%

Exposure to inorganic mercury in vivo attenuates extrinsic apoptotic signaling in Staphylococcal aureus enterotoxin B stimulated T-cells

Laiosa

Eckles

Langdon

et al. 2007

Toxicology and Applied Pharmacology

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The heavy metal mercury (Hg) is known to have immunomodulatory properties affecting lymphocyte signal transduction, death receptor signaling and autoimmunity. In this study we tested the hypothesis that Hg exposure would attenuate T-cell activation and caspase 8 and 3 activity in response to antigenic stimuli. To test this hypothesis, BALB/cJ mice were exposed to 10 mg/L mercuric chloride (HgCl 2 ) in their drinking water for two weeks followed injection with 20μg of the Staphylococcal aureus enterotoxin B (SEB) superantigen. Eighteen hours after SEB challenge, there was a statistically significant reduction in caspase 8 and caspase 3 enzyme activity in the SEB reactive Vβ8+ T-cells. The attenuated caspase activity in Hg exposed mice persisted for 48 hours after exposure. Moreover, activation of caspase 8 and caspase 3 was reduced by more than 60% in CD95 deficient MRL/MpJ-Fas lpr mice demonstrating caspase 8 and 3 activation in response to SEB is CD95 dependent. In addition to the effects of Hg on caspase activity, expression of the T-cell activation marker CD69 was also attenuated in SEB reactive Vβ8 T-cells in Hg-exposed mice. Moreover, CD69 expression in MRL/MpJ-Fas lpr mice was also reduced. Taken together the caspase and CD69 data support a role for CD95 in promoting a proapoptotic and activated state in SEB responsive T-lymphocytes and this state is attenuated by the autoimmune potentiating environmental agent mercury.

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Section: Introductionsupporting

confidence: 82%

Exposure to inorganic mercury in vivo attenuates extrinsic apoptotic signaling in Staphylococcal aureus enterotoxin B stimulated T-cells

Laiosa

Eckles

Langdon

et al. 2007

Toxicology and Applied Pharmacology

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“…It is likely that apoptosis plays an important role in maintaining hepatocyte turnover in the adult liver. Indeed targeted mutation of fas, that mediates Fas ligand-induced apoptosis, results in liver hyperplasia caused by an accumulation of senescent hepatocytes (Adachi et al, 1995).…”

Section: Transcription Factors Have Important Roles In Liver Growth Amentioning

confidence: 99%

Transcriptional regulation of liver development

Duncan¹

2000

Dev. Dyn.

102

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“…Tumor necrosis factor-alpha (TNFa) is a pleiotropic cytokine, which transduces death and survival signaling through its cognate receptors TNFR1 and TNFR2, whereas Fas is a death receptor, which was first characterized as a key initiator of programmed cell death in liver and immune cells (Adachi et al, 1995). Fas initiates many of the same signaling pathways as TNFa, including assembly of death-inducing signaling complexes, activation of nuclear factor kappa B, mitogen-activated protein kinases, Jun N-kinase, receptor-interacting protein, and others.…”

Section: Introductionmentioning

confidence: 99%

TNF Alpha and Fas Mediate Tissue Damage and Functional Outcome after Traumatic Brain Injury in Mice

Bermpohl

You

et al. 2007

J Cereb Blood Flow Metab

113

116

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Tumor necrosis factor-alpha (TNFa) and Fas are induced after traumatic brain injury (TBI); however, their functional roles are incompletely understood. Using controlled cortical impact (CCI) and mice deficient in TNFa, Fas, or both (TNFa/FasÀ/À), we hypothesized that TNFa and Fas receptor mediate secondary TBI in a redundant manner. Compared with wild type (WT), TNFa/FasÀ/À mice had improved motor performance from 1 to 4 days (P < 0.05), improved spatial memory acquisition at 8 to 14 days (P < 0.05), and decreased brain lesion size at 2 and 6 weeks after CCI (P < 0.05). Protection in TNFa/FasÀ/À mice from histopathological and motor deficits was reversed by reconstitution with recombinant TNFa before CCI, and TNFaÀ/À mice administered anti-Fas ligand antibodies had improved spatial memory acquisition versus similarly treated WT mice (P < 0.05). Tumor necrosis factor-alpha/FasÀ/À mice had decreased the numbers of cortical cells with plasmalemma damage at 6 h (P < 0.05 versus WT), and reduced matrix metalloproteinase-9 activity in injured brain at 48 and 72 h after CCI. In immature mice subjected to CCI, genetic inhibition of TNFa and Fas conferred beneficial effects on histopathology and spatial memory acquisition in adulthood (both P < 0.05 versus WT), suggesting that the beneficial effects of TNFa/Fas inhibition may be permanent. The data suggest that redundant signaling pathways initiated by TNFa and Fas play pivotal roles in the pathogenesis of TBI, and that biochemical mechanisms downstream of TNFa/Fas may be novel therapeutic targets to limit neurological sequelae in children and adults with severe TBI.

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Targeted mutation in the Fas gene causes hyperplasia in peripheral lymphoid organs and liver

Cited by 356 publications

References 48 publications

Exposure to inorganic mercury in vivo attenuates extrinsic apoptotic signaling in Staphylococcal aureus enterotoxin B stimulated T-cells

Exposure to inorganic mercury in vivo attenuates extrinsic apoptotic signaling in Staphylococcal aureus enterotoxin B stimulated T-cells

Transcriptional regulation of liver development

TNF Alpha and Fas Mediate Tissue Damage and Functional Outcome after Traumatic Brain Injury in Mice

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