FAS-ligand

Suda et al. 1993

The FAS ligand, abbreviated FasL, is the physiological ligand of the CD95 receptor (Fas is the acronym for: FS7-associated cell surface antigen), also called CD178 or CD95-L, is a type II transmembrane glycoprotein belonging to the TNF superfamily of cytokines , consisting of 281 amino acids and a molecular weight of 31 kDa. The FAS ligand induces programmed cell death (apoptosis) after interaction with the FAS receptor(also called FASR) and also causes Ca2+-independent cytotoxicity. In humans, the FAS ligand is encoded by the FASLG gene, which is located on chromosome 1 at gene locus q24.3.

The FAS ligand, like all members of the TNF superfamily, possesses a characteristic TNF homology domain (THD) that enables binding to the cysteine-rich domains (CRD) of the CD95 receptor. Furthermore, FasL contains a domain in the extracellular C-terminal region that is required for self-aggregation and trimerization. In contrast to the ubiquitous CD95 receptor, the Fas ligand is mainly found at the cell surface of activated CD8+ cytotoxic T lymphocytes and natural killer cells.

Apoptosis: In interaction with its receptor, it mediates apoptosis of infected and transformed cells. In addition, FAS ligand is detectable on the surface of epithelial cells, macrophages and dendritic cells under inflammatory conditions. So, too, in severe drug reactions.

The synthesis of FASL is tightly regulated at the different levels of transcription and translation and, in combination with the limited expression pattern, protects against uncontrolled cell and tissue damage.

Soluble FAS ligand: An additional regulatory mechanism is the so-called shedding of the membrane-bound FAS ligand (mFASL). In this context, MMP3 (matrix metalloprotease-3), MMP7, MMP9 or even ADAM-10 (a disintegrin and metalloprotease-10) mediate the cleavage of mFASL. This results in the release of soluble Fas ligand (sFasL) into surrounding tissues and the bloodstream (Cheng J et al. 1994). As sFasL, the cytokine has a molecular weight of 26 kDa. Unusually high concentrations of soluble Fas ligand are detected in leukemia / lymphoma of T and NK cells and in aggressive nasal lymphoma. The Fas / Fas ligand system is also involved in CD4 + T cell deletion observed in human immunodeficiency virus infected individuals, multiple sclerosis and acute GvHD. Many factors suggest that Fas and FasL interacting with CD8+ cytotoxic T cells should be considered as central mechanisms in the pathogenesis of severe drug responses (Hertl M 2018).

In contrast to the pro-apoptotic effect of mFAsL, sFASL is not able to induce apoptosis. sFasL rather competes with the membrane-bound form for binding to the CD95 receptor (FasR) and induces a signaling pathway leading to proliferation and cell migration. However, when at least two homotrimeric sFasL molecules are linked together, a hexameric structure is formed that now mediates apoptotic signaling like mFasL (Desbarats J et al. 2000).

Proliferation and differentiation of cells: CD95 has been shown to induce proliferation, migration and differentiation under specific conditions and in different cell systems. For example, after partial hepatectomy, non-apoptotic signaling pathways are activated, inducing liver regeneration. In this situation, stimulation with CD95-specific antibodies does not lead to cell death of hepatocytes but promotes their regeneration (Desbarats J et al. 2000). In the central nervous system, CD95-specific monoclonal antibodies also cause accelerated regeneration of damaged neurons. In addition, CD95 induces enhanced expression of a neuron-specific growth factor (p35) through activation of ERK (extracellular-signal regulated kinase).

Furthermore, FASL/FASR interactions play a significant role in the regulation of the immune system and the progression of malignant cells. Tumor cells may prove resistant to FasL-mediated apoptosis. This may be due to downregulation of Fas receptor expression. However, resistance can also occur when very large numbers of Fas receptors are present on the cell surface. Here, disruption of apoptotic signaling occurs at the level of the death-inducing signaling complex (DISC), preventing activation of initiator caspases. Because of these resistances, recombinant FasL is not a useful antitumor strategy.

CD95 stimulation can also mediate anti-apoptotic signals in T lymphocytes. It has been shown that ligation of the CD95 receptor upon costimulation with anti-CD3 antibodies leads to activation and proliferation of freshly isolated human T lymphocytes (Alderson MR et al 1993). Evidence continues to show a dose-dependent modulation of CD95-induced T cell activation. High concentrations of CD95 agonists blocked CD3/CD28-induced activation of human CD4+ T cells.

Mutationsin the FASL gene: Mutations in the FasL gene have been detected in "autoimmune lymphoproliferative syndrome (ALPS)," which can also occur in patients with SLE (Wu et al. 1996).

Increased functional polymorphisms in the promoter region of the FasL gene can also be detected in lung carcinoma. Compared to normal individuals, the risk of developing lung cancer is 1.6-fold increased in the FAS -1377AA genotype (Zhang et al. 2005).

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