Disease relevance of Fas

• The role of Fas in autoimmune diabetes [1].
• Excised neovascular membranes from patients with age-related macular degeneration demonstrated a pattern of Fas+ new vessels in the center of the vascular complex, surrounded by FasL+ retinal pigment epithelial cells [2].
• We have previously demonstrated a role for Fas and Fas ligand (FasL) in the pathogenesis of experimental allergic encephalomyelitis (EAE) [3].
• In both rheumatoid arthritis and animal models of autoimmune arthritis, high levels of Fas are expressed on activated synovial cells and infiltrating leukocytes in the inflamed joints [4].
• These results suggest that the Fas-Fas ligand pathway plays an essential role in the development of pulmonary fibrosis and that preventing this pathway could have therapeutic value in lung injury and fibrosis [5].
• Disruption of IRF8 function with IRF8 dominant-negative mutants diminished Fas-mediated apoptosis in sarcoma tumor cells [6].
• K1 may contribute to lymphoma development by stimulating cell survival by selectively blocking Fas-mediated apoptosis [7].
• DNBS-induced colitis in Fas/FasL-deficient mice did not result in depletion of colonic Tregs [8].
• Bcl2l11(-/-)Fas(lpr/lpr) mice developed remarkably enhanced and accelerated fatal lymphadenopathy and autoimmunity compared to mice lacking only one of these apoptosis inducers [9].
• Hypoxia causes autocrine activation of CD95 on colorectal tumor cells, thereby promoting local invasion and accelerated metastasis outgrowth in the hypoxic transition zone following RFA [10].

Psychiatry related information on Fas

• Stimulation of natural killer T cells during alcohol consumption induces serious liver injury by a mechanism that involves concomitant signals by Fas and tumor necrosis factor receptor-1 on alcohol-stressed hepatocytes [11].
• ALG-3, a truncated form of the familial Alzheimer's disease gene PS2, confers resistance to TCR- and Fas-induced apoptosis [12].
• Importantly, re-expression of Fas in these cells results in either the complete abolishment of tumor development, or in a significant extenuation of the latency period of tumor outgrowth [13].
• These Id/lpr mice provided an ideal system for studying the relationship between the exogenously and endogenously induced responses because: (1) VHIdCR antibodies have been shown to bind autoantigens in vitro; and (2) serological and molecular reagents exist which can identify and monitor VHIdCR antibody production as disease progresses [14].
• Auditory brainstem response (ABR) audiometry showed normal auditory thresholds in C3H/lpr mice at 4 months of age, but elevated thresholds by 6 months, particularly in the high frequencies [15].

High impact information on Fas

• The Fas/FasL system is responsible for activation-induced cell death but also plays an important role in lymphocyte-mediated killing under certain circumstances [16].
• Virtually all of the measurable cell-mediated cytotoxicity delivered by cytotoxic T lymphocytes and natural killer cells comes from either the granule exocytosis pathway or the Fas pathway [16].
• Analyses of mice deficient in perforin and/or Fas demonstrate that cytolysis is critical for immunity against some, but not all, infections and also reveal the contribution of cytolysis to the pathogenesis of disease [17].
• Most recent evidence suggests that complement also regulates elimination of self-reactive B cells, as breeding of mice that are deficient in C4 or CD21/CD35 with the lupus-prone strain of lpr mice demonstrates an exacerbation of disease due to an increase in autoantibodies [18].
• So far, evidence for a role of Fas-dependent cytotoxicity as a T cell effector mechanism in vivo is lacking [19].

Chemical compound and disease context of Fas

• In conclusion, we speculate that the increased Fas-associated apoptosis detected in mucosal B cells (as opposed to splenic or bone marrow B cells) may be due to increased luminal antigens other than endotoxin, released due to gut barrier integrity breakdown during sepsis [20].
• The present results indicate that cryptorchidism induces apoptotic dell death in germ cells, and that testosterone reduction and the Fas system may not be significantly involved in the apoptosis of male germ cells [21].
• The development of cellular infiltrates, bronchiolar and alveolar epithelial apoptosis, and fibrosis following bleomycin instillation in the lungs in lpr mice and gld mice was similar to their development in wild-type mice [22].
• Interferon-beta-induced activation of c-Jun NH2-terminal kinase mediates apoptosis through up-regulation of CD95 in CH31 B lymphoma cells [23].
• To determine whether the effects of omega3 lipids in autoimmune disease is linked to vitamin E levels, weanling female MRL/lpr and congenic control MRL/++ mice were fed diets containing 10% corn oil (CO) or 10% FO at two levels of vitamin E (75 IU or 500 IU/kg diet) for 4 months [24].

Biological context of Fas

• The Fas cell surface receptor induces apoptosis upon receptor oligomerization [25].
• One member of the tumour necrosis factor receptor (TNFR) family, Fas (also known as CD95 or Apo-1), can trigger cell death and is essential for lymphocyte homeostasis [26].
• These findings indicate that Fas mutations result in a massive up-regulation of FasL which, most likely, results from repetitive exposure to (self) antigen [27].
• Absence of p21 resulted in enhanced Fas/FasL-mediated activation-induced T cell death, increased activation of procaspases 8 and 3, and loss of mitochondrial transmembrane potential [28].
• Binding to Fas is mediated by a conserved sequence in the COOH terminus of the protein [29].

Anatomical context of Fas

• Surprisingly, these transgenic mice showed heightened sensitivity to diabetogenic T cells, which was due to self-destruction of beta cells upon T cell-mediated induction of Fas [1].
• The recombinant gld FasL expressed in COS cells could not induce apoptosis in cells expressing Fas [30].
• In addition, antibody against Fas prevented vascular tube formation of choroidal endothelial cells derived from the eye in a three-dimensional in vitro assay [2].
• We demonstrate that blocking the interactions between lymphocyte function associated (LFA)-1 and intercellular adhesion molecule(ICAM)-1 and ICAM-2 completely suppresses Fas-dependent B cell lysis [31].
• Hepatocytes bear Fas but do not express Bcl-2, a protein that plays, in a number of conditions, a protective role against apoptosis [32].

Associations of Fas with chemical compounds

• Thymocytes from ICE-/- mice were sensitive to apoptosis induced by dexamethasone or ionizing radiation, but were resistant to apoptosis induced by Fas antibody [33].
• Conclusions: Activated natural killer T cells help hepatocyte proliferation and liver regeneration after PHx via the TNF and Fas/Fas-ligand-mediated pathway [34].
• N(G)-methyl-L-arginine acetate partially sensitized hepatocytes to TNF-alpha- and Fas-mediated cell killing [35].
• LF 15-0195 does not demonstrate any significant effect on the postmitochondrial activation of caspases, nor does it modify overall expression of CD95, Fas-associated death domain, and procaspase-8 [36].
• This further supports the hypothesis that Fas and ceramide death pathways are independent in A20 cells [37].

Physical interactions of Fas

• Fas ligand (FasL) is a tumor necrosis factor (TNF)-related type II membrane protein and binds to Fas [30].
• Signaling pathways emanating from Fas are coupled to an activation of the transcription factor AP-1 in cardiomyocytes [38].
• An Annexin-V binding assay was used to evaluate the susceptibility of corneal cells to both Fas-dependent and CD4 T-cell-mediated apoptosis in vitro [39].
• Sertoli cells stimulated with TNF-alpha and IFN-gamma markedly increase the expression of both soluble and membrane-bound Fas in a dose-dependent manner [40].
• Finally, Lck derived from unstimulated Jurkat T cells formed stable complexes with the intracellular domain of the Fas receptor [41].

Regulatory relationships of Fas

• CD28-dependent activation of protein kinase B/Akt blocks Fas-mediated apoptosis by preventing death-inducing signaling complex assembly [42].
• The addition of IFNgamma markedly increased the percentage of cells expressing Fas on the surface of the ECFCs as well as the intensity of Fas expression [43].
• Cellular FLICE-inhibitory protein splice variants inhibit different steps of caspase-8 activation at the CD95 death-inducing signaling complex [44].
• In contrast, PKB requires de novo gene transcription by NF-kappaB to block apoptosis triggered by the Fas death receptor [45].
• This conclusion was supported by the following findings: 1) A 24-h treatment with IL-12 plus IL-18 enhanced Fas expression and annexin staining among basophil precursor-enriched lin(-)c-kit(-) splenocytes [46].
• Knocking down FLIP expression abolishes the ability of Met to inhibit Fas-triggered hepatocyte death, demonstrating the functional requirement of FLIP in HGF anti-apoptotic signals [47].
• Beta-catenin bound to and stimulated the Fas promoter [48].

Other interactions of Fas

• Mice homozygous for lpr (lymphoproliferation) or gld (generalized lymphoproliferative disease) develop lymphadenopathy and suffer from autoimmune disease [30].
• Other proteins, notably Daxx, also bind Fas and presumably mediate a FADD-independent apoptotic pathway [26].
• In the second model, deficiency in CD21/CD35 or C4 combined with CD95 deficiency results in high titers of anti-nuclear antibodies leading to severe lupus-like disease [49].
• Interferon-gamma is required for lupus-like disease and lymphoaccumulation in MRL-lpr mice [50].
• CONCLUSIONS: NO protects hepatocytes from TNF-alpha- and Fas-mediated apoptosis [35].
• Further, mice (Bcl2l11(-/-)Fas(lpr/lpr)) lacking the Bcl-2 pro-apoptotic member, Bim (Bcl2l11(-/-)) and and with an lpr mutation in the gene encoding Fas (Fas(lpr/lpr)) developed severe SLE-like disease by 16 weeks of age unlike Bcl2l11(-/-) or Fas(lpr/lpr) mice [51].

Analytical, diagnostic and therapeutic context of Fas

• The nonapoptotic functions of Fas ligation are incompletely characterized [52].
• In contrast to expectations, we show here that Fas-deficient mice developed less-severe collagen-induced arthritis than did control mice [52].
• Fas-mediated apoptosis, induced when a Fas monoclonal antibody bound to and activated the Fas receptor on these cells, was assessed morphologically and by flow cytometry [53].
• Levels of proteins involved in Fas-mediated apoptosis and cleavage of poly(adenosine diphosphate-ribose) polymerase (PARP), an end product of caspase activation, were determined by immunoblotting [53].
• Only a small percentage of normal human ECFCs express Fas and this is present at a low level as detected by Northern blotting for the Fas mRNA and flow cytometric analysis of Fas protein using a specific mouse monoclonal antibody [43].

References