Soluble Fas Ligand Levels Research Articles

Negative Regulators of Hemopoiesis and Stroma Function in Patients with Myelodysplastic Syndrome

The mechanism that leads to hemopoietic failure in patients with myelodysplastic syndrome (MDS) is not well understood. There is evidence, however, that regulatory molecules such as tumor necrosis factor (TNF)-α, Fas (CD95), and Fas-ligand, which negatively affect hemopoiesis by way of apoptosis are upregulated. Here we analyzed marrow samples from 80 patients with MDS in regard to TNF-α and Fas-ligand levels and a possible correlation with various disease parameters and risk factors. TNF-α levels were elevated in comparison to samples from normal marrow donors, however, no significant correlation with FAB subtype, cytogenetic risk group or score by the International Prognostic Scoring System (IPSS) was observed. However, there was an inverse correlation between the cytogenetic risk category (low, intermediate, high) and levels of soluble Fas-ligand. The major source of TNF-α were mononuclear (non-stromal) cells which appeared to produce TNF-α at maximum levels. Limiting dilution analysis of CD34+ precursor cells showed that individually assayed cells, removed from companion cells that presumably provided negative signals such as TNF-α or Fas-ligand, were able to generate progressively increasing numbers of colonies. Stromal layers derived from MDS marrow did not have an inhibitory effect. In fact, higher colony numbers were obtained from both normal and MDS marrow derived hemopoietic precursors propagated on irradiated stromal layers from MDS marrow than on stromal layers from normal marrow. These results show that substantial numbers of normal hemopoietic precursors persist in MDS marrow. However, differentiation into mature cells is inhibited by negative signals originating from accessory or abnormal hemopoietic precursors in the non-adherent marrow fraction.

Decreased expression of the Fas ligand on peripheral blood mononuclear cells and undetectable levels of soluble Fas ligand in the serum of patients with aplastic anemia and myelodysplastic syndrome

American Journal of HematologyVolume 62, Issue 2 p. 124-125 Letters & CorrespondenceFree Access Decreased expression of the Fas ligand on peripheral blood mononuclear cells and undetectable levels of soluble Fas ligand in the serum of patients with aplastic anemia and myelodysplastic syndrome Kenji Shinohara, Kenji Shinohara Division of Hematology, Department of Medicine, Yamaguchi Prefecture Central Hospital, Hofu, JapanSearch for more papers by this authorToru Takahahi, Toru Takahahi Division of Hematology, Department of Medicine, Yamaguchi Prefecture Central Hospital, Hofu, JapanSearch for more papers by this authorRyohei Nawata, Ryohei Nawata Division of Hematology, Department of Medicine, Yamaguchi Prefecture Central Hospital, Hofu, JapanSearch for more papers by this authorEiichi Oeda, Eiichi Oeda Department of Medicine, Shimonoseki Kosei Hospital, Shimonoseki, JapanSearch for more papers by this author Kenji Shinohara, Kenji Shinohara Division of Hematology, Department of Medicine, Yamaguchi Prefecture Central Hospital, Hofu, JapanSearch for more papers by this authorToru Takahahi, Toru Takahahi Division of Hematology, Department of Medicine, Yamaguchi Prefecture Central Hospital, Hofu, JapanSearch for more papers by this authorRyohei Nawata, Ryohei Nawata Division of Hematology, Department of Medicine, Yamaguchi Prefecture Central Hospital, Hofu, JapanSearch for more papers by this authorEiichi Oeda, Eiichi Oeda Department of Medicine, Shimonoseki Kosei Hospital, Shimonoseki, JapanSearch for more papers by this author First published: 04 October 1999 https://doi.org/10.1002/(SICI)1096-8652(199910)62:2<124::AID-AJH16>3.0.CO;2-JCitations: 3AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat References 1Maciejewski J, Selleri C, Anderson S, Young NS. Fas antigen expression on CD34+ human marrow cells is induced by interferon γ and tumor necrosis factor α and potentiates cytokine-mediated hematopoietic suppression in vitro. Blood 1995; 85: 3183– 3190. Medline 2Hatake K, Tomizuka H, Ikeda M, Tsunoda JI, Hoshino Y, Otsuki T, Kasahara T, Yonehara S, Miura Y. The presence of apoptosis in refractory anemia or myelodysplasia. In: NG Abraham, editor. Molecular Biology of Haematopoiesis. Andover: Intercept; 1994. p 122– 123. 3Suda T, Okazaki T, Naito Y, Yokota T, Arai N, Ozaki S, Nakao K, Nagata S. Expression of the Fas ligand in cells of T cell lineage. J Immunol 1995; 154: 3806– 3813. Medline 4Tanaka M, Suda T, Takahashi T, Nagata S. Expression of the functional soluble form of human Fas ligand in activated lymphocytes. EMBO J 1995; 14: 1129– 1135. Medline 5Tanaka M, Itai T, Adachi M, Nagata S. Downregulation of Fas ligand by shedding. Nat Med 1998; 4: 31– 36. Medline 6Nagata S. Apoptosis by death factor. Cell 1997; 88: 355– 365. Medline 7Selleri C, Maciejewski JP, Sato T, Young NS. Interferon-γ constitutively expressed in the stromal microenvironment of human marrow cultures mediates potent hematopoietic inhibition. Blood 1996; 87: 4149– 4157. Medline 8Katsikis PD, Wunderlich ES, Smith CA, Herzenberg LA. Fas antigen stimulation induces marked apoptosis of T lymphocytes in human immunodeficiency virus-infected individuals. J Exp Med 181: 2029– 2036. Medline Citing Literature Volume62, Issue2October 1999Pages 124-125 ReferencesRelatedInformation

Role of Fas–Fas Ligand Interactions in 2,3,7,8-Tetrachlorodibenzo- p-dioxin (TCDD)-Induced Immunotoxicity: Increased Resistance of Thymocytes from Fas-Deficient (lpr) and Fas Ligand-Defective (gld) Mice to TCDD-Induced Toxicity

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a highly toxic environmental pollutant well known for its toxicity to the thymus. Recent studies from our laboratory demonstrated that TCDD induces apoptosis in thymocytes. In the current study, we investigated the mechanism of TCDD-induced apoptosis. Administration of a single dose of TCDD at 0.1, 1, 5, and 50 μg/kg body wt intraperitoneally, into C57BL/6 +/+ (wild-type) mice caused a dose-dependent decrease in thymic cellularity. In contrast, a similar treatment with TCDD, in Fas-deficient C57BL/6 lpr/lpr (lpr) or Fas-ligand defective C57BL/6 gld/gld (gld), mice failed to induce thymic atrophy at 0.1–5 μg/kg body wt of TCDD. In lpr and gld mice, significant thymic atrophy was seen only at 50 μg/kg body wt of TCDD. Injection of TCDD caused apoptosis only in wild-type but not in lpr or gld mice. The sera from TCDD-treated wild-type mice exhibited increased levels of soluble Fas ligand, inasmuch as incubation of Fas+, but not Fas− cells with the sera, triggered apoptosis. Also, TCDD-induced apoptosis in thymocytes was inhibited both in vitro and in vivo by caspase inhibitors. TCDD treatment caused significant up-regulation in the expression of FasL but not Fas mRNA in the thymocytes of wild-type mice. Also, such thymocytes exhibited marked alterations in the surface markers, characteristic of cells undergoing apoptosis. In contrast, TCDD treatment caused minimal phenotypic changes in thymocytes from lpr and gld mice. Together, the current study demonstrates that Fas–Fas ligand interactions play an important role in TCDD-mediated induction of apoptosis and immunotoxicity.

Evaluation of cases with silicosis using the parameters related to Fas-mediated apoptosis.

To establish a new clinical index for immunological abnormalities occurring in silicosis, several clinical parameters related to Fas-mediated apoptosis; i.e., membrane Fas expression on peripheral blood lymphocytes (mFas), serum soluble Fas levels (sFas), serum soluble Fas ligand levels (sFasL), and soluble/membrane Fas mRNA expression ratios (s/mFas ExR) in peripheral blood mononuclear cells (PBMC) were investigated. Fifty-eight silicosis patients with no clinical symptoms of autoimmune diseases were the subjects of this study. Factor analysis was performed using 12 clinical parameters including four parameters related to Fas-mediated apoptosis. Two common factors were identified. Factor 1 which consisted of the following parameters; duration of exposure, symptomatic dyspnea, PO2, PCO2, and A-aDO2, should be designated as the respiratory factor for cases with silicosis. The parameters of factor 2 were serum IgG, sFas with high factor loading, titer of ANA, sFasL, and s/mFas ExR. These parameters of factor 2 are indicative of the immunological disorders occurring in silicosis cases. Some cases exhibited abnormalities in parameters of factor 2 but not factor 1. The factor analysis clearly demonstrated that the parameters related to Fas-mediated apoptosis should be the most beneficial for predicting the pre-clinical status of complicated autoimmune diseases in silicosis.

Increased levels of soluble Fas ligand in CSF of rapidly progressive HTLV-1-associated myelopathy/tropical spastic paraparesis patients

The interaction of Fas ligand (FasL) with Fas-bearing cells induces apoptosis and contributes to the negative regulation of peripheral T-cell responses. Membrane-bound FasL is cleaved by a matrix metalloproteinase-like enzyme and converted to a soluble form (sFasL). Recent studies suggest that such sFasL can cause systemic tissue damage. Here we report that serum and CSF levels of soluble FasL (sFasL) are markedly higher in three active phase patients with HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). All of these patients showed higher sFasL levels in CSF than in serum. Although the HTLV-1 proviral load of patients showed no correlation with serum or with CSF sFasL, CSF sFasL levels of 14 HAM/TSP patients correlated with the anti-HTLV-1 antibody titer and neopterin concentration in CSF. These results indicate that sFasL mediated mechanisms may contribute to the inflammatory process and subsequent spinal tissue damage seen in HAM/TSP patients.

Immunoregulation in pancreatic cancer patients.

Metastatic pancreatic cancer is one of the most aggressive cancer known in man yet specific antitumor immunity has been demonstrated in lymph nodes draining the sites of pancreatic tumors. Despite this immunity, pancreatic cancer patients suffer a quick demise. To further define tumor immunity in patients with metastatic pancreatic cancer, we sought to characterize helper T cell subsets, serum cytokines, cellular cytotoxicity that is both T-cell and non-T cell mediated, as well as known tumor-derived immunosuppressive products that may be present in their peripheral blood. Significantly heightened levels of interleukin 2 (IL-2), a Th1 cytokine, were found in patients before treatment with chemotherapy while serum IL-10, a Th2 cytokine, were at significantly lower levels than observed in normal donors tested between their fifth and seventh decades of life. IL-10 levels increased progressively with age as a serum-bound protein in normal, healthy donors tested between the ages of 24 through 61. An age associated progression of increased IL-10 levels was not observed in pancreatic cancer patients. Few patients had detectable serum levels of soluble fas ligand but approximately half had elevated levels of a tumor marker, detected with the CA-15.3 assay, known as soluble MUCIN 1 (MUC1). Cell mediated cytotoxicity including T-cell mediated killing of pancreatic tumor cell lines was detected in many patients. These data suggest that pancreatic cancer patients have activated type 1 helper T cells that can support development of cell-mediated immunity, and that their sera contain lowered levels of the "anti-inflammatory" type 2 cytokine, IL-10.

Inhibition of peripheral blood lymphocyte apoptosis by soluble fas ligand in patients with hepatocellular carcinoma.

We monitored apoptosis of peripheral blood lymphocytes (PBL) obtained from patients with various degrees of chronic viral hepatitis, including hepatocellular carcinoma (HCC), in vitro and quantitated the serum levels of soluble Fas ligand (FasL) by ELISA. There was no difference in mean percent PBL mortality. However, in HCC patients, the variance was significantly high (P<0.05), and, unexpectedly, a negative association was found between the PBL mortality and the serum soluble FasL levels (P=0.035). These results suggest the inhibitory effect of serum soluble FasL on apoptosis of PBL, which may explain the induction of immunological abnormalities with the development of HCC.

Elevated circulating levels and cardiac secretion of soluble fas ligand in patients with congestive heart failure

The circulating levels of soluble Fas ligand was increased in patients with advanced congestive heart failure. This study also indicates that the failing heart may contribute to the increased concentration of soluble Fas ligand in patients with congestive heart failure.

Levels of soluble Fas ligand in myocarditis

Serum levels of soluble Fas ligand (sFasL) increased with the severity of congestive heart failure (p <0.01), and the percentages of apoptotic myocytes detected by in situ DNA nick-end labeling were significantly higher in the patients with increased levels of sFasL than in those with normal levels of sFasL (p <0.05). These findings indicated that sFasL may play an important role in pathogenesis of myocarditis.

Levels of soluble fas ligand, hepatocyte growth factor and proinflammatory cytokines in children with fulminant hepatic failure

Levels of soluble fas ligand, hepatocyte growth factor and proinflammatory cytokines in children with fulminant hepatic failure

Soluble fas ligand levels during rejection after paediatric liver transplantation

Soluble fas ligand levels during rejection after paediatric liver transplantation