FasL Expression (fasl + expression)

Distribution by Scientific Domains
Distribution within Medical Sciences


Selected Abstracts


Fas and Fas ligand expression on germinal center type-diffuse large B-cell lymphoma is associated with the clinical outcome

EUROPEAN JOURNAL OF HAEMATOLOGY, Issue 6 2006
Yasushi Kojima
Abstract:, In recent years, diffuse large B-cell lymphoma (DLBCL) has been classified by DNA microarray analysis into the germinal center B-cell-like (GC) type, the activated B-cell-like (ABC) type and type 3. The latter two types can be collectively categorized as the non-GC (NGC) type. From the prognostic perspective, the GC type has a favorable clinical outcome when compared with the NGC type. The protein Fas induces apoptosis of lymphocytes by binding with the Fas ligand (FasL), and escape from such apoptosis is considered to lead to malignant transformation of the cells and unrestricted growth of lymphoma. We proposed a hypothesis that Fas/FasL expression could be possibly related with a better survival of GC type DLBCL and evaluated 69 DLBCL cases immunohistochemically with CD10, Bcl-6, MUM1, Fas and FasL. These lymphomas were classified as GC type (positive for CD10 or Bcl-6 and negative for MUM1) or NGC type. The GC type had a better overall survival rate than the NGC type (P = 0.0723). Among markers as given above, positive CD10 was the most significant prognostic factor for overall survival in total DLBCL (P < 0.05). In the GC type, Fas and FasL expressions were significantly associated with a favorable overall survival (Fas: P < 0.005; FasL: P < 0.05). Hence, Fas or FasL expression might contribute to a better prognosis of this type of DLBCL. [source]


Collagen type,I signaling reduces the expression and the function of human receptor activator of nuclear factor -,B ligand (RANKL) in T,lymphocytes

EUROPEAN JOURNAL OF IMMUNOLOGY, Issue 12 2005
Steve Gendron
Abstract The mechanisms by which ,1 integrins modulate T,cell functions are still poorly defined. We have previously reported that signaling via the collagen type,I (Coll,I) receptor, ,2,1 integrin, inhibited FasL expression and protected Jurkat T,cells from activation-induced cell death (AICD). In this study, we examined whether Coll,I signaling in T,cells also modulates the expression of the human receptor activator of nuclear factor-,B ligand (RANKL), a recently identified TNF family member which has important functions in osteoclastogenesis, cell survival and apoptosis. Our results show that in both Jurkat T,cells and human primary T,cells, Coll,I signaling significantly reduces activation-induced RANKL expression by 50,60%. We also found that RANKL is not involved in AICD but participates in doxorubicin-induced apoptosis of leukemia T,cell lines including Jurkat, CEM and HSB-2. In this respect, Coll,I protected leukemia T,cell lines from doxorubicin-induced apoptosis by inhibiting doxorubicin-induced RANKL expression. Together, our results suggest that by limiting the production of RANKL, Coll,I signaling may contribute to the resistance of leukemia T,cells to chemotherapy. Our study also emphasizes the importance Coll,I signaling may have in the control of RANKL-associated T,cell functions. [source]


Functional alterations of liver innate immunity of mice with aging in response to CpG-oligodeoxynucleotide,

HEPATOLOGY, Issue 5 2008
Toshinobu Kawabata
Immune functions of liver natural killer T (NKT) cells induced by the synthetic ligand ,-galactosylceramide enhanced age-dependently; hepatic injury and multiorgan dysfunction syndrome (MODS) induced by ligand-activated NKT cells were also enhanced. This study investigated how aging affects liver innate immunity after common bacteria DNA stimulation. Young (6 weeks) and old (50-60 weeks) C57BL/6 mice were injected with CpG oligodeoxynucleotides (CpG-ODN), and the functions of liver leukocytes were assessed. A CpG-ODN injection into the old mice remarkably increased tumor necrosis factor (TNF) production in Kupffer cells, and MODS and lethal shock were induced, both of which are rarely seen in young mice. Old Kupffer cells showed increased Toll-like receptor-9 expression, and CpG-ODN challenge augmented TNF receptor and Fas-L expression in liver NKT cells. Experiments using mice depleted of natural killer (NK) cells by anti-asialoGM1 antibody (Ab), perforin knockout mice, and mice pretreated with neutralizing interferon (IFN)-, Ab demonstrated the important role of liver NK cells in antitumor immunity. The production capacities of old mice for IFN-,, IFN-,, and perforin were much lower than those of young mice, and the CpG-induced antitumor cytotoxicity of liver NK cells lessened. Lethal shock and MODS greatly decreased in old mice depleted/deficient in TNF, FasL, or NKT cells. However, depletion of NK cells also decreased serum TNF levels and FasL expression of NKT cells, which resulted in improved hepatic injury and survival, suggesting that NK cells are indirectly involved in MODS/lethal shock induced by NKT cells. Neutralization of TNF did not reduce the CpG-induced antitumor effect in the liver. Conclusion: Hepatic injury and MODS mediated by NKT cells via the TNF and FasL-mediated pathway after CpG injection increased, but the antitumor activity of liver NK cells decreased with aging. (HEPATOLOGY 2008.) [source]


Inflammation and drug hepatotoxicity: Aggravation of injury or clean-up mission?,

HEPATOLOGY, Issue 5 2005
Hartmut Jaeschke
BACKGROUND & AIMS Inflammatory mediators released by nonparenchymal inflammatory cells in the liver have been implicated in the progression of acetaminophen (APAP) hepatotoxicity. Among hepatic nonparenchymal inflammatory cells, we examined the role of the abundant natural killer (NK) cells and NK cells with T-cell receptors (NKT cells) in APAP-induced liver injury. METHODS C57BL/6 mice were administered a toxic dose of APAP intraperitoneally to cause liver injury with or without depletion of NK and NKT cells by anti-NK1.1 monoclonal antibody (MAb). Serum alanine transaminase (ALT) levels, liver histology, hepatic leukocyte accumulation, and cytokine/chemokine expression were assessed. RESULTS Compared with APAP-treated control mice, depletion of both NK and NKT cells by anti-NK1.1 significantly protected mice from APAP-induced liver injury, as evidenced by decreased serum ALT level, improved survival of mice, decreased hepatic necrosis, inhibition of messenger RNA (mRNA) expression for interferon-gamma (IFN-gamma), Fas ligand (FasL), and chemokines including KC (Keratinocyte-derived chemokine); MIP-1 alpha (macrophage inflammatory protein-1 alpha); MCP-1 (monocyte chemoattractant protein-1); IP-10 (interferon-inducible protein); Mig (monokine induced by IFN-gamma) and decreased neutrophil accumulation in the liver. Hepatic NK and NKT cells were identified as the major source of IFN-gamma by intracellular cytokine staining. APAP induced much less liver injury in Fas-deficient (lpr) and FasL-deficient (gld) mice compared with that in wild-type mice. CONCLUSIONS NK and NKT cells play a critical role in the progression of APAP-induced liver injury by secreting IFN-gamma, modulating chemokine production and accumulation of neutrophils, and up-regulating FasL expression in the liver, all of which may promote the inflammatory response of liver innate immune system, thus contributing to the severity and progression of liver injury downstream of the metabolism of APAP and depletion of reduced glutathione (GSH) in hepatocytes. [source]


Fas ligand expressed in colon cancer is not associated with increased apoptosis of tumor cells in vivo

INTERNATIONAL JOURNAL OF CANCER, Issue 2 2003
Aileen Houston
Abstract Expression of Fas ligand (FasL/CD95L) may help to maintain colon cancers in a state of immune privilege by inducing apoptosis of antitumor immune effector cells. Colon tumor-derived cell lines appear to be relatively insensitive to apoptosis mediated by their own or exogenous FasL in vitro, despite expression of cell surface Fas. In our present study, we sought to investigate if FasL upregulated in human colon cancers leads to any increase in apoptosis of the tumor cells in vivo. FasL and Fas receptor (APO-1/CD95) expression by tumor cells were detected immunohistochemically. Apoptotic tumor cell death was detected by immunohistochemistry for caspase-cleaved cytokeratin-18. FasL expression did not correlate with the extent of apoptosis of tumor cells. There was no significant local difference in the frequency of apoptosis of tumor cells between tumor nests that expressed FasL (mean = 2.4%) relative to those that did not (mean = 2.6%) (p = 0.625, n = 10; Wilcoxon signed rank). FasL expressed by the tumor cells appeared to be functional, since FasL expression in tumor nests correlated with diminished infiltration of tumor-infiltrating lymphocytes (TILs). TILs were detected using immunohistochemistry for CD45. Expression of FasL by tumor nests was associated with a mean 4-fold fewer TILs relative to FasL-negative nests (range 2.4,33-fold, n = 10, p < 0.003). Together, our results indicate that colon tumors are insensitive to FasL-mediated apoptosis in vivo. © 2003 Wiley-Liss, Inc. [source]


Participation of the Fas and Fas ligand systems in apoptosis during atrophy of the rat submandibular glands

INTERNATIONAL JOURNAL OF EXPERIMENTAL PATHOLOGY, Issue 1 2007
Shigeru Takahashi
Summary Most acinar cells and some duct cells undergo apoptosis during atrophy of the submandibular gland. The present study was designed to elucidate whether Fas and its receptor ligand (FasL) are involved during apoptotic atrophy of the gland. The excretory duct of the right submandibular gland of rats was doubly ligated with metal clips from 1 to 14 days for induction of gland atrophy. Control rats were untreated. Fas and FasL expression in the atrophied submandibular gland was detected using immunohistochemistry (IHC) and Western immunoblot. Expression of activated caspase 8 and activated caspase 3 was also detected with IHC. Fas-positive acinar and duct cells and FasL-positive duct cells increased in the atrophic glands at 3 and 5 days after duct ligation when apoptotic cells were commonly observed. Thereafter, Fas- and FasL-positive cells declined in number. Patterns of expression of Fas and FasL using Western immunoblots concurred with the IHC results. Activated caspase 8-positive cells were present at every time interval but peaked at 3 and 5 days following duct ligation. The cells showing immunoreaction for activated caspase 3 first appeared on day 3, with the peak in apoptosis, after which they decreased. The results indicate that the Fas/FasL systems likely play an important role in apoptotic pathways during atrophy of the submandibular gland. [source]


Fas ligand and tumour counter-attack in colorectal cancer stratified according to microsatellite instability status

THE JOURNAL OF PATHOLOGY, Issue 1 2003
Julie M Michael-Robinson
Abstract Expression of membrane-bound Fas ligand (FasL) by colorectal cancer cells may allow the development of an immune-privileged site by eliminating incoming tumour-infiltrating lymphocytes (TILs) in a Fas-mediated counter-attack. Sporadic colorectal cancer can be subdivided into three groups based on the level of DNA microsatellite instability (MSI). High-level MSI (MSI-High) is characterized by the presence of TILs and a favourable prognosis, while microsatellite-stable (MSS) cancers are TIL-deficient and low-level MSI (MSI-Low) is associated with an intermediate TIL density. The purpose of this study was to establish the relationship between MSI status and FasL expression in primary colorectal adenocarcinoma. Using immunohistochemistry and a selected series of 101 cancers previously classified as 31 MSI-High, 30 MSI-Low, and 40 MSS, the present study sought to confirm the hypothesis that increased TIL density in MSI-High cancers is associated with low or absent membrane-bound FasL expression, while increased FasL in MSS cancers allows the killing of host TILs. TUNEL/CD3 double staining was also used to determine whether MSS cancers contain higher numbers of apoptotic TILs in vivo than MSI-High or MSI-Low cancers. Contrary to the initial hypothesis, it was found that MSI-High cancers were associated with higher FasL expression (p = 0.04) and a stronger intensity of FasL staining (p = 0.007). In addition, mucinous carcinomas were independently characterized by increased FasL expression (p = 0.03) and staining intensity (p = 0.0005). Higher FasL expression and staining intensity did not correlate with reduced TIL density or increased numbers of apoptotic TILs. However, consistent with the hypothesis that curtailment of the host anti-tumour immune response contributes to the poor prognosis in MSS cancers, it was found that apoptotic TILs were most abundant in MSS carcinomas and metastatic Dukes' stage C or D tumours (p = 0.004; p = 0.046 respectively). This study therefore suggests that MSS colorectal cancers are killing incoming TILs in an effective tumour counter-attack, but apparently not via membrane-bound FasL. Copyright © 2003 John Wiley & Sons, Ltd. [source]


ORIGINAL ARTICLE: Placental Fas/Fas Ligand Expression in Early Pregnancy Losses

AMERICAN JOURNAL OF REPRODUCTIVE IMMUNOLOGY, Issue 1 2008
Emine Seda Guvendag Guven
Problem, The aim of this study was to compare the expression levels of Fas and Fas ligand (FasL) in first-trimester placentas obtained from spontaneous abortions in patients with antiphospholipid antibody syndrome (APS) or factor V (FV) Leiden mutation, compared with values in placentas from induced abortions in patients negative for these conditions. Method of study, We studied explants from 6- to 10-week-old placentas that had been prepared by collagenase digestion from 10 spontaneous abortions from APS-positive patients, nine spontaneous abortions in patients positive for FV Leiden mutation, and 10 induced abortions. All tissues were analyzed by flow cytometry for expression of Fas and FasL. Results, Flow cytometric analysis showed that placental FasL expression was significantly lower in abnormal pregnancies than in normal ones. However, no such difference was observed for Fas expression. Conclusion, FasL on placental cells may be involved in the maintenance of immune privilege, thereby ensuring the safety and growth of placental tissues. Dysregulation of apoptotic mechanisms may play a critical role in spontaneous abortions. [source]


Neuronal FasL Induces Cell Death of Encephalitogenic T Lymphocytes

BRAIN PATHOLOGY, Issue 3 2000
A. Flügel
Apoptosis of inflammatory cells plays a crucial role in the recovery from autoimmune CNS disease. However, the underlying mechanisms of apoptosis induction are as yet ill-defined. Here we report on the neuronal expression of FasL and its potential function in inducing T-cell apoptosis. Using a combination of facial nerve axotomy and passive transfer encephalomyelitis, the fate of CD4+ encephalitogenic T cells engineered to express the gene for green fluorescent protein was followed. FasL gene transcripts and FasL protein were detected in neurons by in situ -hybridization and immunohistochemistry. T cells infiltrating preferentially the injured brain parenchyma were found in the immediate vicinity of FasL expressing neurons and even inside their perikarya. In contrast to neurons, T cells rapidly underwent apoptosis. In co-cultures of hippocampal nerve cells and CD4+ T lymphocytes, we confirmed expression of FasL in neurons and concomitant induction of T-cell death. Antibodies blocking neuronal FasL were shown to have a protective effect on T-cell survival. Thus, FasL expression by neurons in neuroinflammatory diseases may constitute a pivotal mechanism underlying apoptosis of encephalitogenic T cells. [source]


Increased Fas ligand expression by T cells and tumour cells in the progression of actinic keratosis to squamous cell carcinoma

BRITISH JOURNAL OF DERMATOLOGY, Issue 1 2004
A.C. Satchell
Summary Background In the counterattack model of tumorigenesis, it has been proposed that tumours develop resistance to attack from Fas ligand (FasL)-expressing cytotoxic T cells by downregulating Fas (immune escape), while at the same time upregulating FasL expression to induce apoptosis in Fas-expressing T cells (counterattack). Objectives The aim of this study was to examine Fas and FasL expression on tumour cells and infiltrating T cells during the progression of actinic keratoses (AK), the benign precursor lesion, to squamous cell carcinoma (SCC). Patients and methods Samples of AK (n = 20) and SCC (n = 20) were collected from immunocompetent patients attending dermatology clinics. Double-label immunohistochemistry was performed on frozen sections using mouse monoclonal antibodies to Fas or FasL, simultaneously with a rabbit polyclonal antibody to either CD3 or cytokeratin, markers of T cells and keratinocytes, respectively. Cell densities and the optical density of tumour Fas expression were measured using image analysis. Results FasL-expressing T cells were observed in nine of 19 SCCs, compared with three of 20 AKs (P < 0·05). FasL-expressing tumour cells were found in nine of 18 SCCs, compared with only one of 20 AK specimens (P < 0·005). There was no difference in the number of Fas-expressing T cells infiltrating AK and SCC. Fas expression by keratinocytes, measured by optical density, was lower in SCC (range 0·1,40, median 17) compared with AK (range 4,62, median 25) (P < 0·05). Conclusions These results suggest that the greater numbers of FasL-expressing T cells infiltrating into SCC compared with AK are targeting Fas-expressing tumour cells. As AK cells progress to SCC, they subvert this T-cell-mediated killing of tumour cells by downregulating their Fas expression (immune escape). Furthermore, tumour cells upregulate their expression of FasL, possibly as a counterattack measure to induce apoptosis in the increased number of tumour-infiltrating T cells. Thus changes in Fas/FasL-mediated interactions between T cells and tumour cells occur during the progression of AK into SCC. [source]


Fas and Fas ligand expression on germinal center type-diffuse large B-cell lymphoma is associated with the clinical outcome

EUROPEAN JOURNAL OF HAEMATOLOGY, Issue 6 2006
Yasushi Kojima
Abstract:, In recent years, diffuse large B-cell lymphoma (DLBCL) has been classified by DNA microarray analysis into the germinal center B-cell-like (GC) type, the activated B-cell-like (ABC) type and type 3. The latter two types can be collectively categorized as the non-GC (NGC) type. From the prognostic perspective, the GC type has a favorable clinical outcome when compared with the NGC type. The protein Fas induces apoptosis of lymphocytes by binding with the Fas ligand (FasL), and escape from such apoptosis is considered to lead to malignant transformation of the cells and unrestricted growth of lymphoma. We proposed a hypothesis that Fas/FasL expression could be possibly related with a better survival of GC type DLBCL and evaluated 69 DLBCL cases immunohistochemically with CD10, Bcl-6, MUM1, Fas and FasL. These lymphomas were classified as GC type (positive for CD10 or Bcl-6 and negative for MUM1) or NGC type. The GC type had a better overall survival rate than the NGC type (P = 0.0723). Among markers as given above, positive CD10 was the most significant prognostic factor for overall survival in total DLBCL (P < 0.05). In the GC type, Fas and FasL expressions were significantly associated with a favorable overall survival (Fas: P < 0.005; FasL: P < 0.05). Hence, Fas or FasL expression might contribute to a better prognosis of this type of DLBCL. [source]