Fas and Fas Ligand Expressed on Cells of the Immune System, not on the Target Tissue, Control Induction of Experimental Autoimmune Uveitis

Wahlsten, Jennifer L.; Gitchell, Heather L.; Chan, Chi‐Chao; Wiggert, Barbara; Caspi, Rachel R

doi:10.4049/jimmunol.165.10.5480

Cited by 35 publications

(20 citation statements)

References 33 publications

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“…It is clear that Fas/FasL have a fundamental role in the regulation of the immune system. 2,4,5 It is well documented that AICD in peripheral T-cells is mediated through Fas and FasL interaction, and is believed to function as limitation overexpansion of an immune response by eliminating unwanted lymphocytes and elimination autoreactive T-cells during thymic selection. 6 Similar to many cellular cascades, the Fas/ FasL pathway is policed by numerous mediators.…”

Section: Introductionmentioning

confidence: 99%

Let-7/miR-98 regulate Fas and Fas-mediated apoptosis

Tang

Cui

et al. 2011

Genes Immun

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Fas is ubiquitously expressed on a variety of cells and triggers apoptosis, which have critical roles in the immune system. MicroRNAs (miRNAs) have been recently identified as regulators that modulate target gene expression and are involved in diverse biological processes, such as cell proliferation and apoptosis. This study was undertaken to investigate the contribution of miRNA in the regulation of Fas expression and Fas-mediated apoptosis. Bioinformatics analysis indicated that Fas was a potential target of let-7/miR-98 family. Indeed ectopic expression of let-7/miR-98 reduced, whereas knockdown of endogenous let-7/miR-98 increased the expression of Fas at both mRNA and protein levels. Let-7/miR-98 was verified to target Fas 3 0 untranslated region directly by site-directed gene mutagenesis and reporter gene assay. More importantly, introduction of let-7/miR-98 could decrease the sensitivity to Fas-induced apoptosis. Furthermore, let-7/miR-98 expression was reduced in activation-induced cell death process, accompanied by increased expression of Fas. In conclusion, our study first demonstrated that let-7/miR-98 regulated Fas expression and the sensitivity of Fas-mediated apoptosis.

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Section: Introductionmentioning

confidence: 99%

Let-7/miR-98 regulate Fas and Fas-mediated apoptosis

Tang

Cui

et al. 2011

Genes Immun

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“…The absence of either FasL from the eye, or Fas from the lymphocytes, results in a destructive inflammatory response (6,11). This suggests that uveitis might result from insufficient Fas-mediated apoptosis, although paradoxically, both Fas and FasL are required for the induction of experimental autoimmune uveoretinitis (12).…”

mentioning

confidence: 99%

Inhibition of T Cell Apoptosis in the Aqueous Humor of Patients with Uveitis by IL-6/Soluble IL-6 Receptor trans-Signaling

Curnow

Scheel‐Toellner

Jenkinson

et al. 2004

The Journal of Immunology

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A fundamental mechanism of immune privilege in the eye is the induction of T lymphocyte apoptosis. Intraocular inflammation in uveitis implies compromise of immune privilege. This study sought to determine whether apoptosis of T cells is actively inhibited in patients with uveitis and by what pathways this may occur. Apoptotic lymphocytes were found to be absent from aqueous humor (AqH) of virtually all patients with recent-onset uveitis. However, T cells removed from the eye were highly susceptible to both spontaneous and Fas ligand-induced apoptosis in vitro. AqH from patients with uveitis had no modulatory effect on Fas ligand-induced apoptosis, but strongly suppressed survival factor deprivation-induced apoptosis. In contrast, noninflammatory AqH from patients undergoing cataract surgery had no modulatory effects on apoptosis at all. These data suggest that triggering of the Fas pathway is diminished in uveitis, and also that homeostatic resolution through survival factor deprivation-induced apoptosis is inhibited by factors present in AqH. The most widely recognized pathways, common γ-chain cytokines and type I IFNs, did not contribute to AqH-mediated T cell survival. High levels of both IL-6 and soluble IL-6R were found in AqH. IL-6 alone did not induce T cell survival, because IL-6R expression on T cells in AqH was too low to facilitate signaling. However, combinations of IL-6 and soluble IL-6R were highly effective inhibitors of T cell apoptosis, suggesting that the trans-signaling pathway is likely to be a key mediator of T cell apoptosis inhibition mediated by uveitis AqH.

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“…However, a fine balance exists between the removal of legitimate T cell targets, such as virally infected or cancerous cells, and tissue destruction which results when the Fas/FasL pathway is inappropriately activated. Thus, FasL has been implicated in a number of autoimmune diseases such as hepatitis, insulin-dependent diabetes, thyroiditis, and uveitis (7)(8)(9)(10)(11).…”

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confidence: 99%

Inhibition of Metalloproteinase Cleavage Enhances the Cytotoxicity of Fas Ligand

Knox

Milner

Green

et al. 2003

The Journal of Immunology

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The Fas ligand (FasL)/Fas receptor (CD95) pathway is an important mediator of apoptosis in the immune system and can also mediate cancer cell death. Soluble FasL (sFasL), shed from the membrane-bound form of the molecule by a putative metalloproteinase (MP), may function to locally regulate the activity of membrane-bound FasL. Using a replication-defective recombinant adenovirus-expressing FasL (RAdFasL), we identified a variable ability of different carcinoma cells to respond to FasL-induced cytotoxicity and to shed sFasL. Blockade of FasL cleavage with an MP inhibitor significantly enhanced RAdFasL-induced apoptosis suggesting that sFasL may antagonize the effect of membrane-bound FasL. In support of this concept, a recombinant adenovirus expressing a noncleavable form of FasL (RAdD4) was found to be a potent inducer of apoptosis even at very low virus doses. Our results highlight the therapeutic potential of noncleavable FasL as an antitumor agent and emphasize the important role of MP via the production of sFasL in regulating the response of the Fas pathway. Moreover, these findings have general implications for the therapeutic exploitation of TNF family ligands and for the possible impact of MP-based therapies on the normal physiology of Fas/TNF pathways.

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Fas and Fas Ligand Expressed on Cells of the Immune System, not on the Target Tissue, Control Induction of Experimental Autoimmune Uveitis

Cited by 35 publications

References 33 publications

Let-7/miR-98 regulate Fas and Fas-mediated apoptosis

Let-7/miR-98 regulate Fas and Fas-mediated apoptosis

Inhibition of T Cell Apoptosis in the Aqueous Humor of Patients with Uveitis by IL-6/Soluble IL-6 Receptor trans-Signaling

Inhibition of Metalloproteinase Cleavage Enhances the Cytotoxicity of Fas Ligand

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