Inhibition of Metalloproteinase Cleavage Enhances the Cytotoxicity of Fas Ligand

Knox, Pauline G.; Milner, Andrew; Green, Nicky K.; Eliopoulos, Aristides G.; Young, Lawrence S.

doi:10.4049/jimmunol.170.2.677

Cited by 49 publications

(48 citation statements)

References 58 publications

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“…Over the past years, it became evident that FasL might also be released by protease cleavage to act as a soluble cytokine. 8 34 Several MMPs including MMP-3 (stromelysin-1) 35 and MMP-7 (matrilysin) 9,16 have been associated with FasL cleavage in different cellular systems. On the other hand, several other members of the TNF-family and TNF receptor family are proteolytically processed by ADAMs, suggesting that these proteases might also be involved in the FasL cleavage.…”

Section: Discussionmentioning

confidence: 99%

ADAM10 regulates FasL cell surface expression and modulates FasL-induced cytotoxicity and activation-induced cell death

et al. 2007

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The apoptosis-inducing Fas ligand (FasL) is a type II transmembrane protein that is involved in the downregulation of immune reactions by activation-induced cell death (AICD) as well as in T cell-mediated cytotoxicity. Proteolytic cleavage leads to the generation of membrane-bound N-terminal fragments and a soluble FasL (sFasL) ectodomain. sFasL can be detected in the serum of patients with dysregulated inflammatory diseases and is discussed to affect Fas-FasL-mediated apoptosis. Using pharmacological approaches in 293T cells, in vitro cleavage assays as well as loss and gain of function studies in murine embryonic fibroblasts (MEFs), we demonstrate that the disintegrin and metalloprotease ADAM10 is critically involved in the shedding of FasL. In primary human T cells, FasL shedding is significantly reduced after inhibition of ADAM10. The resulting elevated FasL surface expression is associated with increased killing capacity and an increase of T cells undergoing AICD. Overall, our findings suggest that ADAM10 represents an important molecular modulator of FasL-mediated cell death.

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Section: Discussionmentioning

confidence: 99%

ADAM10 regulates FasL cell surface expression and modulates FasL-induced cytotoxicity and activation-induced cell death

et al. 2007

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“…In the second, FasL is anchored to intracellular membrane microvesicles, where it is stored until expressed on the cell surface in response to physiological stimuli. The last corresponds to a soluble FasL, which is generated by degradation of the membranous shape (during the first minutes of expression) due to the activity of a metalloprotease matrix whose function is to catalyze the degradation of extracellular matrix proteins (108)(109)(110)(111). The soluble FasL molecule has either pro-apoptotic or antiapoptotic properties since soluble FasL is an inefficient homotrimer binding to Fas.…”

Section: Fas-fasl Intercellular Linkage-mediated Pathwaymentioning

confidence: 99%

“…On the contrary, soluble FasL can induce apoptosis after its association or aggregation with extracellular matrix proteins. In addition, apoptosis is induced when soluble FasL forms tetramers or highly arranged structures (111). Fas/FasL pathway plays an important role in graft rejection (112), where soluble FasL can be chemotactic to neutrophils, during the acute rejection of a graft transplant (113).…”

Section: Fas-fasl Intercellular Linkage-mediated Pathwaymentioning

confidence: 99%

Cell Death Mechanisms Induced by Cytotoxic Lymphocytes

et al. 2009

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One of the functions of the immune system is to recognize and destroy abnormal or infected cells to maintain homeostasis. This is accomplished by cytotoxic lymphocytes. Cytotoxicity is a highly organized multifactor process. Here, we reviewed the apoptosis pathways induced by the two main cytotoxic lymphocyte subsets, natural killer (NK) cells and CD8 + T cells. In base to recent experimental evidence, we reviewed NK receptors involved in recognition of target-cell, as well as lytic molecules such as perforin, granzymes-A and -B, and granulysin. In addition, we reviewed the Fas-FasL intercellular linkage mediated pathway, and briefly the cross-linking of tumor necrosis factor (TNF) and TNF receptor pathway. We discussed three models of possible molecular interaction between lytic molecules from effector cytotoxic cells and target-cell membrane to induction of apoptosis. Cellular & Molecular Immunology. 2009;6(1):15-25.

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“…In addition, overexpression of MMP-7 is believed to promote mammary tumour initiation and progression in mice by selecting for tumour cells resistant to Fas-mediated apoptosis [132]. Cells expressing low levels of a noncleavable variant of Fas ligand or inhibition of matrix metalloproteinases increases the sensitivity to Fas-mediated apoptosis [133]. Thus, MMP-7 can control the expression of Fas ligand on the surface of adjacent cells and infiltrating lymphocytes by cleaving membrane-bound Fas ligand.…”

Section: Modulators Of Fas Receptor and Fas Ligand Expressionmentioning

confidence: 99%