The Role of Fas-FasL in the Development and Treatment of Ischemic Retinopathy

Barreiro, Ramon; Schadlu, Ramin; Herndon, John M.; Kaplan, Henry J.; Ferguson, T.

doi:10.1167/iovs.02-0478

Cited by 45 publications

(31 citation statements)

References 16 publications

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“…Several pathways have been suggested to explain the antiangiogenic activity of PEDF, such as inducing EC death by activating the Fas/FasL death pathway (31). However, PEDF still inhibits neovascularization in mice lacking either Fas or FasL (54), implying that either other pathways are involved or that PEDF does not use Fas-FasL interactions to inhibit retinal neovascularization. Following this hypothesis, other groups have reported that MAPK JNK and p38 influence EC apoptosis by modulating c-FLIP or caspase activity (32,33).…”

Section: Discussionmentioning

confidence: 99%

Laminin Receptor Involvement in the Anti-angiogenic Activity of Pigment Epithelium-derived Factor

Bernard

Gao-Li²,

Franco³

et al. 2009

Journal of Biological Chemistry

151

131

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Pigment epithelium-derived factor (PEDF) is a multifunctional protein with neurotrophic, anti-oxidative, and anti-inflammatory properties. It is also one of the most potent endogenous inhibitors of angiogenesis, playing an important role in restricting tumor growth, invasion, and metastasis. Studies show that PEDF binds to cell surface proteins, but little is known about how it exerts its effects. Recently, research identified phospholipase A 2 /nutrin/patatin-like phospholipase domaincontaining 2 as one PEDF receptor. To identify other receptors, we performed yeast two-hybrid screening using PEDF as bait and discovered that the non-integrin 37/67-kDa laminin receptor (LR) is another PEDF receptor. Co-immunoprecipitation, His tag pulldown, and surface plasmon resonance assays confirmed the interaction between PEDF and LR. Using the yeast two-hybrid method, we further restricted the LR-interacting domain on PEDF to a 34-amino acid (aa) peptide (aa 44 -77) and the PEDF-interacting domain on LR to a 91-aa fragment (aa 120 -210). A 25-mer peptide named P46 (aa 46 -70), derived from 34-mer, interacts with LR in surface plasmon resonance assays and binds to endothelial cell (EC) membranes. This peptide induces EC apoptosis and inhibits EC migration, tube-like network formation in vitro, and retinal angiogenesis ex vivo, like PEDF. Our results suggest that LR is a real PEDF receptor that mediates PEDF angiogenesis inhibition.Pigmented epithelium-derived factor (PEDF), 2 also known as SERPIN F1 and EPC1, is a 50-kDa serpin-like peptide. Although first identified in cultured pigment epithelial cells from fetal human retinas (1), we now know that liver, kidney, heart, testis, and lung tissues also express PEDF (2). PEDF influences many biological processes. It is anti-angiogenic, anti-tumorigenic, anti-inflammatory, anti-oxidative, neurotrophic, and neuroprotective, and it exhibits anti-vasopermeability properties (3-9). These diverse actions affect many cell types, including retinal cells (10), neuronal cells (11), endothelial cells (12), and hematopoietic stem cells (13). X-ray diffraction studies show that PEDF has an asymmetrical charge distribution (14). A high density of basic residues on one side of the molecule (positive) interact with heparin and glycosaminoglycans, whereas acidic residues on the opposite side (negative) interact with type-1 collagen (15)(16)(17)(18)(19)). Yet the mechanisms explaining the diverse biological activities of PEDF remain unclear.A ligand/receptor interaction at the cell membrane seemed likely, in addition to interactions within extracellular matrices, because of the diverse effects and ubiquitous expression of PEDF and the fact that most PEDF deposits remain within extracellular matrices (20). We suspected that distinct PEDF receptors elicit divergent signals to cause different biological effects. Indeed, evidence shows that PEDF binds at least two receptors: a 60-kDa receptor in ECs and an 80-kDa receptor in neuronal cells (21)(22)(23)(24). Research has identified two functional epi...

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Section: Discussionmentioning

confidence: 99%

Laminin Receptor Involvement in the Anti-angiogenic Activity of Pigment Epithelium-derived Factor

Bernard

Gao-Li²,

Franco³

et al. 2009

Journal of Biological Chemistry

151

131

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“…The gld and lpr mutations were bred onto the BALB/c background by crossing B6-gld and B6-lpr (originally obtained from The Jackson Laboratory) to BALB/c for a minimum of 10 generations. Mice were screened by PCR as described (20). Because the mutations were derived from B6 mice, these strains are designated C.B6-lpr and C.B6-gld.…”

Section: Micementioning

confidence: 99%

Peripheral Deletion of Antigen-Specific T Cells Leads to Long-Term Tolerance Mediated by CD8+ Cytotoxic Cells

Herndon

Stuart

Ferguson

2005

The Journal of Immunology

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Peripheral deletion is one mechanism by which potentially self-reactive clones are removed whether they escape thymic deletion. We have examined the consequences of deleting Ag-specific T cells by i.v. injection of soluble Ag. Deletion of DO11.10 T cells by peptide was mediated predominately via a Fas/FasL mechanism. Animals that underwent deletion were tolerant to subsequent immunization with Ag, even when tolerant mice were given fresh Ag-specific DO11.10 T cells before immunization. Tolerance was mediated by CD8+ T cells that killed the DO11.10-transgenic T cells in vivo. These data demonstrate that the programmed cell death of large numbers of T cells leads to peripheral tolerance mediated by CD8+ CTLs.

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“…The gld and lpr mutations were bred onto the BALB/c background by crossing B6-gld and B6-lpr (originally obtained from The Jackson Labortory, Bar Harbor, ME) to BALB/c for a minimum of 10 generations. Mice were screened by PCR as described (28). Since the mutations were derived from B6 mice these strains are designated C.B6-lpr and C.B6-gld.…”

Section: Micementioning

confidence: 99%

Termination of Antigen-Specific Immunity by CD95 Ligand (Fas Ligand) and IL-10

Barreiro

Luker

Herndon

et al. 2004

The Journal of Immunology

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Following elimination of a foreign invader, the immune system must return to its normal quiescent levels. This process requires removal of reactive immune cells when they are no longer needed. We have explored the role of Fas/Fas ligand (FasL) in terminating immunity and demonstrate that mice defective in these proteins have prolonged immune responses. Studies demonstrate that termination of immunity occurs via the interaction of Fas+ lymphoid cells with FasL+ nonlymphoid cells at the site of Ag challenge. Our results also show that FasL is absent in quiescent tissue but is rapidly up-regulated during the local immune reaction. This occurs through the production of IL-10. Thus, FasL and IL-10 work in concert to eliminate inflammatory cells and control the duration of an immune response.

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The Role of Fas-FasL in the Development and Treatment of Ischemic Retinopathy

Abstract: Fas-FasL interactions regulate the extent of oxygen-induced retinal neovascularization. The inhibition of neovascularization in B6 gld, and B6-lpr mice by PEDF suggests that Fas-FasL interactions are probably not the mechanism for inhibition in this model.

Cited by 45 publications

References 16 publications

Laminin Receptor Involvement in the Anti-angiogenic Activity of Pigment Epithelium-derived Factor

Laminin Receptor Involvement in the Anti-angiogenic Activity of Pigment Epithelium-derived Factor

Peripheral Deletion of Antigen-Specific T Cells Leads to Long-Term Tolerance Mediated by CD8+ Cytotoxic Cells

Termination of Antigen-Specific Immunity by CD95 Ligand (Fas Ligand) and IL-10

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