The membrane-bound but not the soluble form of human Fas ligand is responsible for its inflammatory activity

Shudo, Koyo; Kinoshita, Koichi; Imamura, Ryu; Fan, Hong; Hasumoto, Kenyu; Tanaka, Masato; Nagata, Shinji; Suda, Takafumi

doi:10.1002/1521-4141(200108)31:8<2504::aid-immu2504>3.0.co;2-c

Cited by 80 publications

(46 citation statements)

References 25 publications

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“…This can perhaps be attributed to the elevation of mCD95L and neutrophils during this phase. mCD95L is primarily believed to be responsible for the inflammatory activity of CD95L 7 and its absence may reduce apoptotic activity in rodents. 21 Shortly after SCI, mCD95L and apoptotic markers are elevated.…”

Section: Discussionmentioning

confidence: 99%

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Increase in soluble CD95L during subacute phases after human spinal cord injury: a potential therapeutic target

et al. 2012

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Study design: A pilot study measuring the levels of serum-soluble CD95 ligand (CD95L) in eight spinal cord-injured patients. Objectives: To determine the soluble concentration of CD95L in spinal cord injury (SCI) patients after trauma. Methods: We collected blood samples from eight patients with acute traumatic SCI. Soluble CD95L serum levels were determined using an enzyme-linked immunosorbent assay. American Spinal Injury Association (ASIA) was determined according to ASIA classification. The patients were monitored, and venous blood was drawn after arrival at the hospital on the 1st and 3rd day and during the 1st, 2nd, 4th, 8th and 12th weeks after trauma. Results: The average patient age was 48.1 years (18-86 years). Three patients were paraplegic (two incomplete, one complete), five were quadriplegic (one complete, four incomplete). The serum concentration of soluble CD95L (sCD95L) decreased during the 1st week (41 ng l À1 ) and increased after the 2nd week in all eight patients. It peaked during the 4th week (68.5 ng l À1 ) and reached a plateau during the 12th week (76.2 ng l À1 ). There are many possible explanations for not being able to detect a statistical significance, one of course being the small sample size. Conclusion: Promising results for anti-CD95L therapy have already been documented in lab studies with rodents. Anti-CD95L blocks the pro-apoptotic and proinflammatory activity of membrane-bound CD95L during the acute phase of SCI. We observed that sCD95L levels are elevated during the subacute and intermediate phases of SCI. It would be of great interest to study a larger group of patients to determine whether higher sCD95 levels are correlated with improved or impaired neurological outcome or with increasing levels of autoimmune components in peripheral blood.

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Section: Discussionmentioning

confidence: 99%

“…6 sCD95L cannot trigger apoptosis, but induces the production of proinflammatory chemokine in neutrophils. 7 Therapeutic neutralization of CD95L significantly decreased apoptotic cell death after SCI. 8 Rodents treated with CD95L-specific antibodies were capable of initiating active hind-limb movements several weeks after injury.…”

Section: Introductionmentioning

confidence: 99%

Increase in soluble CD95L during subacute phases after human spinal cord injury: a potential therapeutic target

et al. 2012

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“…The use of FasL as a priming agent offers a unique advantage, since it can not only promote apoptosis of susceptible tumor cells, but also has robust proinflammatory properties that promote rejection of Fas-resistant tumors, as well as protective immune responses to subsequent challenge with those tumors. [10][11][12][13][16][17][18] The cause of death for dogs 1, 3, and 5 was verified by a licensed veterinarian. Dog 2 died while sleeping and a necropsy was not performed.…”

Section: Discussionmentioning

confidence: 99%

“…Our group and others have shown that malignant cells that do not express Fas, or that express Fas mutants with signaling defects and are resistant to FasL-dependent apoptosis in vitro, fail to form tumors in mice if they are transduced with membrane-bound FasL. 10,11,13,[16][17][18][19][20][21] The unusual antitumor properties of FasL, therefore, appear to offer a major advantage in its application for cancer therapy. For this study, we examined the capability to induce apoptosis of canine melanoma cells in vitro by overexpression of FasL, and we assessed the safety of in vivo administration of FasL in a Phase I clinical trial that included five dogs with spontaneous malignant melanoma (World Health Organization (WHO) stage III or IV).…”

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confidence: 99%

Enhancing antimelanoma immune responses through apoptosis

et al. 2003

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We examined the feasibility of using tumor apoptosis at accessible sites to enhance antimelanoma immune responses in a model of spontaneous canine melanoma. We show that priming peripheral blood mononuclear cells with apoptotic melanoma cells significantly enhanced autologous and allogeneic lymphokine-activated killing of tumor cells. Since various pathways required for intrinsic apoptosis are often inactivated in melanoma, we used Fas ligand (FasL) overexpression to promote extrinsic apoptosis. FasL induced apoptosis in five of six cell lines. Each of the susceptible lines, but not the resistant one, expressed Fas mRNA. In addition, direct intratumoral administration of FasL DNA to tumor-bearing dogs was safe, with no adverse events reported over 7 days of observation. A reduction of tumor burden was seen in three of five dogs treated. The reduction of tumor volume was correlated with Fas expression by the tumors, although one dog with a Fas-negative tumor survived for 82 weeks after treatment. Our data show that overexpression of FasL is suitable to promote apoptosis of Fas + melanomas, and support the notion that priming immune responder cells with apoptotic tumor cells may enhance antitumor responses. The results also suggest that intratumoral administration of FasL offers a safe route for therapeutic gene delivery.

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“…The activity (units) of soluble FasL was determined by its cytotoxic activity against W4.5 cells overexpressing mouse Fas, as described previously (19). An anti-mouse FasL mAb (FLIM58) was established and purified, as described previously (20).…”

Section: Reagentsmentioning

confidence: 99%

Pathogen-Associated Molecular Patterns Sensitize Macrophages to Fas Ligand-Induced Apoptosis and IL-1β Release

Fukui

Imamura

Umemura

et al. 2003

The Journal of Immunology

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Antigenic stimulation activates T cells and simultaneously destines them to die by Fas-mediated apoptosis. In this study, we demonstrated that various pathogen-associated molecular patterns up-regulated Fas expression in macrophages and sensitized them specifically to Fas ligand (FasL), but not to other apoptosis-inducing agents such as TNF-α, etoposide (VP-16), and staurosporine. Toll-like receptor, NF-κB, and p38 mitogen-activated protein kinase mediated these responses. LPS stimulation induced the expression of Fas, caspase 8, cellular FLIP Bfl-1/A1, and Bcl-x, but not FasL, TNFR p55, Bak, Bax, and Bad at the transcriptional level. Thus, LPS selectively induced the expression of apoptotic molecules of the Fas death pathway (except for cellular FLIP) and antiapoptotic molecules of the mitochondrial death pathway. However, the kinetics of macrophage disappearance following Escherichia coli-induced peritonitis was similar between wild-type and Fas-deficient mice, suggesting that Fas is not essential for the turnover of activated macrophages in T cell-independent inflammation. In contrast, LPS-activated macrophages produced a large amount of IL-1β upon FasL stimulation. Thus, unlike the activation-induced cell death of T cells, the sensitization of macrophages to FasL by pathogen-associated molecular patterns seems to be a proinflammatory rather than an anti-inflammatory event.

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The membrane-bound but not the soluble form of human Fas ligand is responsible for its inflammatory activity

Cited by 80 publications

References 25 publications

Increase in soluble CD95L during subacute phases after human spinal cord injury: a potential therapeutic target

Increase in soluble CD95L during subacute phases after human spinal cord injury: a potential therapeutic target

Enhancing antimelanoma immune responses through apoptosis

Pathogen-Associated Molecular Patterns Sensitize Macrophages to Fas Ligand-Induced Apoptosis and IL-1β Release

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