Disease relevance of Fasl

• Germline mutations in Fas and Fasl induce nonmalignant T cell hyperplasia and systemic autoimmunity and also greatly increase the risk of B cell neoplasms [1].
• Par-4 drives trafficking and activation of Fas and Fasl to induce prostate cancer cell apoptosis and tumor regression [2].
• Mice homozygous for lpr (lymphoproliferation) or gld (generalized lymphoproliferative disease) develop lymphadenopathy and suffer from autoimmune disease [3].
• 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 [4].
• Administration of Propionibacterium acnes (P. acnes) upregulated functional Fas expression on macrophages in an IFNgamma-dependent manner, and these macrophages became competent to secrete mature IL-18 upon stimulation with FasL [5].
• These results point to a role for myocarditis regulation by Fas/Fas-L beyond its possible direct relevance in cellular death [6].
• Although truncating Fas-FasL signaling ameliorates many untoward effects of sepsis, the pathological mode of action is distinct at the tissue level [7].
• Partial disruption of FasL protects from autoimmune diabetes without causing T-cell lymphoproliferation [8].
• In a nontumor-bearing colitis model in vivo, neutrophil recruitment to the intestine was also reduced in gld/gld mice [9].

Psychiatry related information on Fasl

• These cytokines and FasL are involved in host defense mechanisms against tumors [10].

High impact information on Fasl

• The autosomal recessive lpr and gld genes induce in mice multiple autoantibodies and the progressive accumulation of large numbers of non-malignant CD4- CD8- T lymphocytes [11].
• Lpr and gld: single gene models of systemic autoimmunity and lymphoproliferative disease [11].
• The gld gene is located on chromosome 1; its product is also unknown [11].
• Foreign antigens that stimulate the BCR acutely cause CD40L and FasL to promote clonal proliferation [12].
• Generalized lymphoproliferative disease in mice, caused by a point mutation in the Fas ligand [3].

Chemical compound and disease context of Fasl

• We have found that penicillic acid (PCA) inhibits FasL-induced apoptosis and concomitant loss of cell viability in Burkitt's lymphoma Raji cells [13].
• 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 [14].
• Infusion of lysophosphatidylcholine, a component of oxidized low density lipoprotein, markedly decreased apoptotic cell clearance in gld mice, indicating that hypercholesterolemia promotes autoimmune disease in this background [15].
• CD95L-induced glioma cell apoptosis does not involve ceramide generation [16].
• IL-18-binding protein protects against lipopolysaccharide- induced lethality and prevents the development of Fas/Fas ligand-mediated models of liver disease in mice [17].

Biological context of Fasl

• The second cytolytic effector system relies on the interaction of the Fas ligand (Fasl) on the effector cell with its receptor (Fas) on the target cell, leading to apoptotic cell death [18].
• Here, mouse Fasl gene was isolated and localized to the gld region of mouse chromosome 1 [3].
• The mouse Fas-ligand gene is mutated in gld mice and is part of a TNF family gene cluster [19].
• These findings indicate that Fas mutations result in a massive up-regulation of FasL which, most likely, results from repetitive exposure to (self) antigen [20].
• Fas-deficient lpr and gld mice develop lymphadenopathy due to the accumulation of T cells with an unusual double negative (DN) (CD4-CD8-) phenotype [20].

Anatomical context of Fasl

• Evidence for selective transformation of autoreactive immature plasma cells in mice deficient in Fasl [1].
• The expression of Fas ligand (Fasl), transforming growth factor (TGF)-beta1 and clusterin on Sertoli cells were detected by immunocytochemistry [21].
• The recombinant gld FasL expressed in COS cells could not induce apoptosis in cells expressing Fas [3].
• Here, we investigated caspase-1-independent processing of IL-18 in Fas ligand (FasL)-stimulated macrophages and its involvement in liver injury [5].
• We found that FasL expressed on donor cells is important for the development of EAE, as FasL-deficient lymphocytes transfer attenuated disease [22].

Associations of Fasl with chemical compounds

• Regulation of fas ligand expression during activation-induced cell death in T cells by p38 mitogen-activated protein kinase and c-Jun NH2-terminal kinase [23].
• 9-cis retinoic acid inhibition of activation-induced apoptosis is mediated via regulation of fas ligand and requires retinoic acid receptor and retinoid X receptor activation [24].
• We report here that 9-cis RA inhibits T-cell receptor-mediated apoptosis in T-cell hybridomas by blocking the expression of Fas ligand following activation [24].
• These results suggest that ceramide does not induce apoptosis through the Fas/FasL pathway [25].
• Furthermore, in the thymi of 5-FU-treated animals, CD95L was strongly up-regulated [26].

Physical interactions of Fasl

• Fas ligand (FasL) is a tumor necrosis factor (TNF)-related type II membrane protein and binds to Fas [3].
• Fas ligand binding on oocytic fas may result in caspase 8 activation [27].
• Here, we show that mice lacking both NFATp and NFAT4 develop a profound lymphoproliferative disorder likely due to a lowered threshold for TCR signaling coupled with increased resistance to apoptosis secondary to defective FasL expression [28].
• The ability to prevent rejection was minimally affected by the presence of a defect in Fas ligand binding or by the absence of granzyme B but was severely affected by the absence of perforin [29].
• In support of this hypothesis, cytokine gene-engineered DCs expressed higher levels of MHC and costimulatory molecules, as well as Fas ligand and membrane-bound tumor necrosis factor alpha, with the latter markers associated with elevated tumoricidal activity in vitro [30].

Regulatory relationships of Fasl

• Pathogen-associated molecular patterns sensitize macrophages to Fas ligand-induced apoptosis and IL-1 beta release [31].
• Furthermore, virus-immune CTL with functional FasL and perforin (gzmAxB(-/-)) are more potent in causing target cell apoptosis in vitro than those expressing FasL alone (perfxgzmAxB(-/-)) [32].
• Both CD95L and anti-CD95 antibodies triggered caspase activation followed by apoptotic death in fully pro-inflammatory astrocytes, whereas resting cells were totally resistant [33].
• Gene transfection studies using NF-kappaB-dependent reporter plasmid showed that FasL did activate NF-kappaB promoter activity [34].
• Stimulation of microglial metabotropic glutamate receptor mGlu2 triggers tumor necrosis factor alpha-induced neurotoxicity in concert with microglial-derived Fas ligand [35].

Other interactions of Fasl

• Thymuses from nur77/N10-transgenic mice on a gld/gld background have increased cellularity and an almost normal profile of thymocyte subpopulations [36].
• These findings illustrate that RNS cause cell death in a Fas- and JNK-dependent manner and that this occurs through a pathway distinct from FasL [37].
• Our results show that primary mixed lymphocyte reaction (MLR)-derived CTLs from granzyme B-/- x gld/gld mice induce apoptosis of allogeneic targets with less efficiency and a longer delay than CTLs deficient for granzyme B alone [38].
• In these models, T cell-mediated tumor regression and long-term antitumor immunity are perforin and FasL independent [39].
• In addition, macrophages either deficient in FasL or lacking p53 showed resistance to the effect of morphine [40].
• Hematopoietic stem and progenitor cells are insensitive to Fas-mediated apoptosis and thus can exploit the constitutive expression of FasL to exert potent veto activities in the early stages of engraftment [41].

Analytical, diagnostic and therapeutic context of Fasl

• Northern blot analysis revealed that lymph node cells obtained from lpr and gld mice had a striking increase in the level of expression of FasL mRNA predominantly due to expression in the DN T cells [20].
• To assess whether some of the apoptosis known to occur after ionizing radiation might be mediated by Fas/Fas ligand (FasL) interactions, we quantitated in vitro apoptosis by flow cytometry measurement of DNA content in splenic T and B cells from irradiated 5- to 8-month-old B6/lpr mice [42].
• Inhibition of both TNF and CD95L in vitro prevented death of primary neurons induced by oxygen-glucose deprivation and reperfusion [43].
• Gene transcripts for FasL were identified in single murine hippocampal neurons by RT-PCR combined with patch clamp electrophysiology, and constitutive expression of FasL protein was confirmed in neurons by immunohistochemistry [44].
• The approach taken was to compare the therapeutic efficacy of wild-type to FasL-deficient (gld) CTL clones by adoptive transfer [45].

References