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The Journal of Immunology, 1998, 161: 4484-4488.
Copyright © 1998 by The American Association of Immunologists

CUTTING EDGE

Cutting Edge: Chemotactic Activity of Soluble Fas Ligand Against Phagocytes1

Ken-ichiro Seino2,3,*,{dagger}, Kazuhisa Iwabuchi3,{ddagger}, Nobuhiko Kayagaki*, Ryukou Miyata{ddagger}, Isao Nagaoka{ddagger}, Akio Matsuzawa§, Katashi Fukao{dagger}, Hideo Yagita*,¶ and Ko Okumura*,¶

* Department of Immunology, Juntendo University School of Medicine, Tokyo, Japan; {dagger} Department of Surgery, University of Tsukuba School of Medicine, Ibaraki, Japan; {ddagger} Department of Biochemistry, Juntendo University School of Medicine, Tokyo, Japan; § Laboratory Animal Research Center, Institute of Medical Science, University of Tokyo, Tokyo, Japan; and Core Research for Evolutional Science and Technology, Japan Science and Technology Corporation, Tokyo, Japan


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
A recombinant soluble form of human Fas ligand (sFasL) was tested for its chemotactic activity against human and mouse polymorphonuclear neutrophils (PMN) by the Boyden chamber method. sFasL exhibited a potent chemotactic activity against both human and mouse PMN and HL-60 cells when differentiated into neutrophils or monocytes. A neutralizing anti-FasL mAb abolished the chemotactic activity, while control mAb did not. Ligation of Fas by either IgM- or IgG-type anti-Fas mAb also induced PMN migration. PMN derived from lpr mice that express few Fas molecules did not respond to sFasL. In contrast, those derived from lprcg mice that express Fas molecules with a mutated death domain normally responded to sFasL chemotaxis. These results directly indicated a chemotactic activity of sFasL against PMN and suggest a novel signaling function of Fas, which appears to be independent of the death domain-mediated apoptosis.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
The Fas ligand (FasL)4 belongs to the TNF family, which includes TNF, lymphotoxin, TNF-related apoptosis-inducing ligand (TRAIL), CD40 ligand, CD27 ligand, CD30 ligand, and OX40 ligand (1). Most members of the TNF family, except for lymphotoxin-{alpha}, are type II membrane proteins. However, a soluble form of FasL (sFasL) is naturally produced by metalloproteinase-mediated processing such as TNF-{alpha} (2, 3). The physiologic roles of the shedding of TNF family members have not been well characterized.

FasL induces apoptotic cell death by binding to its receptor, Fas (also called APO-1 or CD95), which is a member of the TNF receptor family (4). FasL is predominantly expressed in activated T cells and NK cells, while Fas is ubiquitously expressed on various cells. FasL-mediated cell death is involved in the T or NK cell-mediated cytotoxicity, some pathologic tissue damages, and the regulation of lymphocyte homeostasis (4). FasL is also expressed in the testis (5), eye (6), and some malignant tumor cells (7, 8), which has been proposed to contribute to their immune-privileged status. FasL expressed in such immune-privileged tissues may eliminate infiltrating immune cells. By applying this concept, Lau et al. reported that syngeneic myoblasts expressing FasL protected allogeneic pancreatic islets from immune rejection when cotransplanted under the kidney capsule (9).

In contrast, we and others have found that enforced FasL expression in tumor cells or islets elicited neutrophilic inflammation and destruction of the graft. When implanted s.c. or i.p., various tumor cells expressing FasL induced neutrophil infiltration and rapid rejection (10). Similarly, expression of functional FasL in the pancreatic islets of FasL-transgeneic mice induced granulocytic infiltrates and damage of the islets (11, 12). In this context, we here verified the chemotactic activity of FasL against polymorphonuclear neutrophils (PMN). A novel signaling function of Fas, which appears to be independent of the functional death domain, was noted.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Preparation of sFasL

A recombinant soluble form of human FasL (sFasL) was produced by using the baculovirus expression system as described previously (13). Briefly, the full-length FasL cDNA was subcloned into PVL1393 (PharMingen, San Diego, CA) and transfected into Spodoptera frugiperda (SF9) cells according to the manufacturer’s instruction. The culture supernatant was applied to an affinity column of protein Sepharose A conjugated with an anti-FasL (NOK-1) mAb (2). The bound sFasL was eluted with 0.1 M glycine-HCl buffer (pH 4.0). The concentration of sFasL was determined by sandwich ELISA as described previously (2).

Preparation of PMN

C3H/He wild-type and lpr mice were purchased from SLC (Shizuoka, Japan). CBA lprcg mice, which have a loss-of-function mutation in the death domain of the Fas molecule (14), had been backcrossed 12 times to C3H mice, and the C3H lprcg mice were maintained in the animal facilities of Tokyo University and used for the experiments. Mouse PMN were isolated from peritoneal exudates 4–5 h after an i.p. injection of 3 ml 4% thioglycollate (Difco, Detroit, MI) as described previously (15). Mouse PMN preparations contained >87% Gr-1+ cells as estimated by flow cytometry. Human PMN were isolated from citrate-anticoagulated peripheral blood of healthy donors by Polymorphoprep (Nycomed Pharma, Oslo, Norway) centrifugation techniques as described previously (16). The purity of human PMN was >95% as estimated by Wright-Giemsa stain. PMN were suspended in PBS containing 1 mM CaCl2 and 1 mM MgSO4.

Cell culture

Human promyelocytic leukemia HL-60 cells were maintained in RPMI 1640 medium (Nissui, Tokyo, Japan) containing 10% FBS, 2 mM glutamine, 100 µg/ml streptomycin, and 100 U/ml penicillin. To differentiate HL-60 cells into neutrophilic or monocytic lineage, the cells were cultured with 1.3% DMSO or 5 nM PMA for 4 days, respectively (17, 18), and then used for the chemotaxis assay. The differentiation was confirmed by Wright-Giemsa stain of cytospin preparations and expression of cell surface CD11b (17, 18).

Chemotaxis assay

Cell migration was assayed by employing a modified Boyden chamber with cellulose nitrate filter, as described previously (19). We used a 3-µm pore size filter for PMN and untreated or DMSO-treated HL-60 cells and a 5-µm pore size filter for PMA-treated HL-60 cells. Varying concentrations of purified sFasL, anti-Fas mAb (CH-11 (IgM, Medical Biologic Laboratories, Nagoya, Japan) or DX-2 (IgG1, PharMingen)), or control mAb (mouse IgM or IgG1, PharMingen) in PBS supplemented with 1 mM Ca2+, Mg2+, and 1 mg/ml BSA (Fraction V, Sigma, St. Louis, MO) were added to the upper or lower wells of the chamber. One million cells in 250 µl PBS supplemented with 1 mM Ca2+, Mg2+, and 1 mg/ml BSA were placed into the upper wells. The entire apparatus was incubated at 37°C for 45 min for PMN and untreated or DMSO-treated HL-60 cells, and 90 min for PMA-treated HL-60 cells. The membrane was then fixed with neutral buffered formalin for 30 min and stained with hematoxylin, hematoxylin and eosin, or Wright-Giemsa. With a x40 objective, the distance (µm) from the top of the filter to the furthest two cells at the same focal plane was measured microscopically. This measure was taken for 10 fields across the filter. In each assay, human IL-8 (Genzyme, Cambridge, MA) or FMLP was used as a positive control. For a blocking experiment, anti-FasL mAb (NOK-1) (2) or control mAb (mouse IgG1, PharMingen) at a concentration of 10 µg/ml was added to both upper and lower chambers.

Statistical analysis

The statistical significance of differences from control was evaluated by Student’s t test. Values of p < 0.05 were considered significant.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
We first evaluated the ability of sFasL to induce human PMN migration across the cellulose nitrate filters. The mean data from three individual experiments is shown in Fig. 1GoA. Significant PMN migration for sFasL ranging from 0.1 to 10 nM was observed, although the positive chemoattractant IL-8 was more active. sFasL as well as IL-8 showed a bell-shaped chemotactic activity. When the same concentration of sFasL was added to both upper and lower chambers, the PMN migration was not observed, indicating that chemokinetic movement of PMN was not enhanced. A neutralizing mAb to FasL, but not control mAb (data not shown), abolished the FasL-induced migration, indicating that the PMN migration was indeed induced by FasL but not by some contaminant in the rsFasL preparation.



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  		FIGURE 1. sFasL and anti-Fas mAbs induce human PMN migration. A, Effect of sFasL on human PMN migration. IL-8 and sFasL (0.001–1000 nM) were assessed for chemotactic activity against human peripheral blood PMN by the Boyden chamber method. The column designated as 1/1 represents the presence of sFasL (1 nM) in both upper and lower chambers. For blocking, anti-FasL mAb or control mAb (10 µg/ml) was added to both upper and lower chambers. B, Effect of anti-Fas mAbs on human PMN migration. Control mouse IgM and IgG1 mAbs (1 µg/ml) and anti-Fas mAbs (CH-11 (IgM) and DX-2 (IgG1) 0.01–10 µg/ml) were assessed for chemotactic activity against human PMN. *, p < 0.05; **, p < 0.01 compared with negative control (cont.). ns, Not significant. Data are shown as mean ± SD of three independent experiments using different donors.

 
Because it was possible that Fas/FasL interaction might trigger the production of some chemotactic factor responsible for the chemotaxis, we obtained supernatant of human PMN that had undergone chemotaxis to sFasL and tested its chemotactic activity against PMN in the presence of anti-FasL mAb. However, the supernatant failed to induce chemotaxis (data not shown), excluding this possibility.

To characterize the cells undergoing chemotaxis to sFasL, we stained the filters with hematoxylin and eosin or Wright-Giemsa. The migrating cells had no eosinophilic or basophilic granules (not shown), indicating that the cells undergoing chemotaxis were neutrophils.

Next, we examined whether ligation of Fas by anti-Fas mAb might also induce PMN migration. We used IgM (CH-11)- or IgG (DX-2)-type anti-Fas mAbs, which are cytotoxic or noncytotoxic in solution, respectively. As indicated in Fig. 1GoB, not only cytotoxic CH-11 but also noncytotoxic DX-2 induced PMN migration, suggesting that the signal transduction for the chemotaxis may be different from that for apoptosis.

It has been well characterized that a human promyelocytic leukemia cell line HL-60 can be differentiated into neutrophils or monocytes in the presence of DMSO or PMA, respectively (17, 18). Untreated, DMSO-treated, and PMA-treated HL-60 cells expressed Fas at a comparable level as estimated by FACS analysis (data not shown). Then, we examined the ability of sFasL to induce migration of the HL-60 cells that were differentiated into neutrophilic or monocytic lineage. As shown in Fig. 2Go, A and B, both untreated and DMSO-treated HL-60 cells significantly responded to sFasL. Similarly, PMA-treated HL-60 cells also responded to sFasL (Fig. 2GoC). These results suggest that sFasL has a chemotactic activity against not only neutrophils but also monocytes.



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  		FIGURE 2. Effect of sFasL on migration of undifferentiated or differentiated HL-60. FMLP (10 nM) and sFasL (0.1–10 nM) were assessed for chemotactic activity against untreated (A), DMSO-treated (B), and PMA-treated (C) HL-60 cells. *, p < 0.05; **, p < 0.01 compared with negative control (cont.). ns, Not significant. Data are shown as mean ± SD of three independent experiments.

 
Further, we evaluated the ability of sFasL to induce mouse PMN migration. As shown in Fig. 3GoA, sFasL ranging from 0.1 to 10 nM induced as potent a migration as did IL-8 when PMN were obtained from wild-type C3H mice. The chemokinetic movement of neutrophils was not enhanced as in Fig. 1GoA. The anti-FasL mAb, but not control mAb (data not shown), abolished the FasL-induced migration. The chemotactic activity of sFasL was not observed against PMN obtained from the lpr mice, which lack Fas (Fig. 3GoB), indicating that the FasL-induced PMN migration is mediated through Fas on PMN. In contrast, as shown in Fig. 3GoC, PMN obtained from the lprcg mice responded to sFasL almost comparably to those from wild-type mice, suggesting that the signal transduction for cell migration may not need a functional death domain in the cytoplasmic region of Fas.



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  		FIGURE 3. Effect of sFasL on mouse PMN migration. IL-8 (20 nM) and sFasL (0.1–10 nM) were assessed for chemotactic activity against thioglycollate-elicited PMN obtained from wild-type (A), lpr (B), or lprcg (C) mice. The column designated as 1/1 represents the presence of sFasL (1 nM) in both upper and lower chambers. For blocking, anti-FasL mAb or control mAb (10 µg/ml) was added to both upper and lower chambers. *, p < 0.05; **, p < 0.01 compared with negative control (cont.). ns, Not significant. Data are shown as mean ± SD of three independent experiments.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
In the present study, we demonstrated that sFasL acts as a chemoattractant against human and mouse PMN in vitro. This conclusion is consistent with our in vivo observation that FasL transfectants injected in syngeneic mice induced neutrophil infiltration and rejection of the cells (10). The FasL-induced rejection appeared to be dependent upon the expression of Fas on the host leukocytes, because wild-type->lpr, but not lpr->wild-type, bone marrow chimeras rejected the FasL transfectants with neutrophilic infiltrates (10). Therefore, it has been speculated that FasL might directly act on infiltrating cells that were mainly composed of neutrophils. Although the present study does not exclude a possible contribution of other indirect mechanisms, it is strongly suggested that the chemotactic action of sFasL is directly involved in the FasL-induced inflammation in vivo.

We used human sFasL in this study. We and other groups demonstrated that mouse FasL also induced a similar inflammation (10, 11, 12). Although mouse sFasL has been shown to have little cytotoxic activity (3), it may have another function such as chemotaxis, which remains to be determined in further studies. Recently, several groups demonstrated a greatly reduced cytotoxic activity of sFasL as compared with membrane-bound FasL (20, 21, 22), arguing against a systemic cytotoxic role of sFasL. Consistently, the sFasL preparation used in this study did not enhance the apoptosis of Jurkat cells (13) and PMN (data not shown) after several hours of incubation. Our present results suggest that sFasL can act proinflammatory by recruiting PMN rather than proapoptotically in certain pathophysiologic conditions.

Recently, signaling pathways for Fas-mediated apoptosis have been extensively characterized. Recruitment of FADD/Mort-1 and activation of caspase-8 mediate apoptosis through the activation of down-stream caspases (23). Fas can also induce apoptosis through RIP and RAIDD followed by caspase-2 activation (24), or through Daxx followed by jun kinase activation (25). In contrast, signaling for Fas-mediated inflammation has not been characterized. So far, it has been demonstrated that crosslinking of Fas by Ab could induce activation of the transcription factor NF-{kappa}B (26, 27) and secretion of IL-8 (28) in certain cell lines. In this study, both IgM- and IgG-type anti-Fas mAbs induced PMN migration (Fig. 1GoB). Although it is generally believed that trimerization of Fas is needed for the induction of apoptosis, these results suggest that trimerization may not be necessary for the induction of chemotaxis, but dimerization of Fas may be sufficient. Furthermore, in the present study the chemotaxis was normally induced in PMN obtained from lprcg mice (Fig. 3GoC) whose Fas molecules have a point mutation in the death domain and cannot induce apoptosis due to the inability to recruit FADD or RIP (14). These data suggest that some other signaling components may be recruited to the Fas molecules independently of the known death domain-interacting molecules for the chemotactic activity, which remained to be identified in further studies.

It has been shown that soluble human TNF-{alpha} has a chemotactic activity against human PMN in vitro (29, 30). The chemotactic activity of sFasL demonstrated in this study appears to be comparable to that of TNF-{alpha} described in these studies. Thus, it will be interesting to see whether other members in the TNF family have similar function. It has been reported that low concentrations of TNF-{alpha} act synergistically with IL-1 to induce neutrophil infiltration in vivo (31). Similarly, it is possible that low concentrations of sFasL may enhance proinflammatory function of other cytokines. Actually, sFasL has been detected in the sera of patients suffering from some inflammatory diseases such as systemic lupus erythematosus (32), rheumatoid arthritis (32), Sjogren’s syndrome (32), leukemia (33), lymphohistiocytosis (34), myocarditis (35), and alcoholic liver disease (36). Recently, Hashimoto et al. (37) reported that sFasL was detected in the joints of patients with rheumatoid arthritis, where neutrophil influx is often observed. The sFasL was produced by lymphocytes in the synovial fluid, and cleaved sFasL accumulated in the inflamed joints. They also reported that the concentration of sFasL was remarkably higher in patients with severe rheumatoid arthritis than in patients with its mild form. Further clinical studies may elucidate the pathophysiologic role of sFasL at a local site of inflammation in other diseases.


   Footnotes
 
1 This work was supported by grants from the Science and Technology Agency, the Ministry of Education, Science and Culture, and the Ministry of Health, Japan. K.S. is a research fellow of the Japan Society for the Promotion of Science. Back

2 Address correspondence and reprint requests to Dr. Ken-ichiro Seino, Department of Surgery, University of Tsukuba School of Medicine, 1-1-1 Tennodai, Tsukuba Science-City, Ibaraki 305-8575, Japan. E-mail address: Back

3 The first two authors contributed equally to this work. Back

4 Abbreviations used in this paper: FasL, Fas ligand; sFasL, soluble FasL; PMN, polymorphonuclear neutrophils. Back

Received for publication June 1, 1998. Accepted for publication August 24, 1998.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

  1. Nagata, S.. 1997. Apoptosis by death factor. Cell 88:355.[Medline]
  2. Kayagaki, N., A. Kawasaki, T. Ebata, H. Ohmoto, S. Ikeda, S. Inoue, K. Yoshino, K. Okumura, H. Yagita. 1995. Metalloproteinase-mediated release of human Fas ligand. J. Exp. Med. 182:1777.[Abstract/Free Full Text]
  3. Tanaka, M., T. Suda, T. Takahashi, S. Nagata. 1995. Expression of the functional soluble form of human Fas ligand in activated lymphocytes. EMBO J. 14:1129.[Medline]
  4. Nagata, S., P. Golstein. 1995. The Fas death factor. Science 267:1449.[Abstract/Free Full Text]
  5. Bellgrau, D., D. Gold, H. Selawry, J. Moore, A. Franzusoff, R. C. Duke. 1995. A role for CD95 ligand in preventing graft rejection. Nature 377:630.[Medline]
  6. Griffith, T. S., T. Brunner, S. M. Fletcher, D. R. Green, T. A. Ferguson. 1995. Fas ligand-induced apoptosis as a mechanism of immune privilege. Science 270:1189.[Abstract/Free Full Text]
  7. Hahne, M., D. Rismolde, M. Schroter, P. Romero, M. Screier, L. E. French, P. Schneider, T. Bornand, A. Fontana, D. Lienard, et al 1996. Melanoma cell expression of Fas(Apo-1/CD95) ligand: implications for tumor immune escape. Science 274:1363.[Abstract/Free Full Text]
  8. Strand, S., W. J. Hofmann, H. Hug, M. Muller, G. Otto, D. Strand, S. M. Mariani, W. Stremel, P. H. Krammer, P. R. Galle. 1996. Lymphocyte apoptosis induced by CD95 (APO-1/Fas) ligand-expressing tumor cells: a mechanism of immune evasion?. Nature Med. 2:1361.[Medline]
  9. Lau, H. T., M. Yu, A. Fontana, Jr C. J. Stoeckert. 1996. Prevention of islet allograft rejection with engineered myoblasts expressing FasL in mice. Science 273:109.[Abstract]
  10. Seino, K., N. Kayagaki, K. Okumura, H. Yagita. 1997. Antitumor effect of locally produced CD95 ligand. Nature Med. 3:165.[Medline]
  11. Allison, J., H. M. Georgiou, A. Strasser, D. L. Vaux. 1997. Transgenic expression of CD95 ligand on islet ß cells induces a granulocytic infiltration, but does not confer immune privilege upon islet allografts. Proc. Natl. Acad. Sci. USA 94:3943.[Abstract/Free Full Text]
  12. Kang, S.-M., D. B. Schneider, Z. Lin, D. Hanahan, D. A. Dichek, P. G. Strock, S. Baekkeskov. 1997. Fas ligand expression in islets of Langerhans does not confer immune privilege and instead targets them for rapid destruction. Nature Med. 3:738.[Medline]
  13. Oyaizu, N., N. Kayagaki, H. Yagita, S. Pahwa, Y. Ikawa. 1997. Requirement of cell-cell contact in the induction of Jurkat cell apoptosis: the membrane-anchhored but not soluble form of FasL can trigger anti-CD3-induced apoptosis in Jurkat T cells. Biochem. Biophys. Res. Commun. 238:670.[Medline]
  14. Matsuzawa, A., T. Moriyama, T. Kaneko, M. Tanaka, M. Kimura, H. Ikeda, T. Katagiri. 1990. A new allele of the lpr locus, lprcg, that complements the gld gene in induction of lymphadenopathy in the mouse. J. Exp. Med. 171:519.[Abstract/Free Full Text]
  15. Bogen, S., J. Pak, M. Garifallou, X. Deng, W. A. Muller. 1994. Monoclonal antibody to murine PECAM-1 (CD31) blocks acute inflammation in vivo. J. Exp. Med. 179:1059.[Abstract/Free Full Text]
  16. Iwabuchi, K., I. Nagaoka, A. Someya, T. Yamashita. 1996. Type IV collagen-binding proteins of neutrophils: possible involvement of L-selectin in the neutrophil binding to type IV collagen. Blood 87:365.[Abstract/Free Full Text]
  17. Hickstein, D., A. Smith, W. Fisher, P. Beatty, B. Schwartz, J. Harlan, R. Root, R. Locksley. 1987. Expression of leukocyte adherence-related glycoproteins during differentiation of HL-60 promyelocytic leukemia cells. J. Immunol. 138:513.[Abstract]
  18. Bohnsack, J., J. Chang. 1994. Activation of ß 1 integrin fibronectin receptors on HL60 cells after granulocytic differentiation. Blood 83:543.[Abstract/Free Full Text]
  19. Zigmond, S. H., J. G. Hirsch. 1972. Effects of cytocalasin B on polymorphonuclear leukocyte locomotion, phagocytosis and glycolysis. Exp. Cell. Res. 73:383.[Medline]
  20. Tanaka, M., T. Itai, M. Adachi, S. Nagata. 1998. Downregulation of Fas ligand by shedding. Nature Med. 4:31.[Medline]
  21. Suda, T., H. Hashimoto, M. Tanaka, T. Ochi, S. Nagata. 1997. Membrane Fas ligand kills human peripheral blood T lymphocytes, and soluble Fas ligand blocks the killing. J. Exp. Med. 186:2045.[Abstract/Free Full Text]
  22. Schneider, P., N. Holler, J. L. Bodmer, M. Hahne, K. Frei, A. Fontana, J. Tschopp. 1998. Conversion of membrane-bound Fas (CD95) ligand to its soluble form is associated with downregulation of its proapoptotic activity and loss of liver toxicity. J. Exp. Med. 187:1205.[Abstract/Free Full Text]
  23. Medema, J. P., C. Scaffidi, F. C. Kischkel, A. Shevchenko, M. Mann, P. H. Krammer, M. Peter. 1997. FLICE is activated by association with the CD95 death-inducing signaling complex (DISC). EMBO J. 16:2794.[Medline]
  24. Duan, H., V. M. Dixit. 1997. RAIDD is a new "death" adaptor molecule. Nature 385:86.[Medline]
  25. Yang, X., R. Khorsravi-Far, H. Y. Chang, and D. Baltimore. 1997. Daxx, a novel Fas-binding protein that activates JNK and apoptosis. Cell 1067.
  26. Rensing-Ehl, A., S. Hess, H. Ziegler-Heitbrock, G. Riethmuller, H. Engelmann. 1995. Fas/Apo-1 activates nuclear factor {kappa} B and induces interleukin-6 production. J. Inflamm. 45:161.[Medline]
  27. Ponton, A., M. Clement, I. Stamenkovic. 1996. The CD95 (APO-1/Fas) receptor activates NF-{kappa}B independently of its cytotoxic function. J. Biol. Chem. 271:8991.[Abstract/Free Full Text]
  28. Abreu Martin, M. T., A. Vidrich, D. H. Lynch, S. R. Targan. 1995. Divergent induction of apoptosis and IL-8 secretion in HT-29 cells in response to TNF-{alpha} and ligation of Fas antigen. J. Immunol. 155:4147.[Abstract]
  29. Ming, W., L. Bersani, A. Mantovani. 1987. Tumor necrosis factor is chemotactic for monocytes and polymorphonuclear leukocytes. J. Immunol. 138:1469.[Abstract]
  30. Figari, I., N. Mori, J. Palladino MA. 1987. Regulation of neutrophil migration and superoxide production by recombinant tumor necrosis factor-{alpha} and ß: comparison to recombinant interferon-{gamma} and interleukin-1{alpha}. Blood 70:979.[Abstract/Free Full Text]
  31. Sayers, T., T. Wiltrout, C. A. Bull, 3rd A. C. Denn, A. M. Pilaro, B. Lokesh. 1988. Effect of cytokines on polymorphonuclear neutrophil infiltration in the mouse: prostaglandin- and leukotriene-independent induction of infiltration by IL-1 and tumor necrosis factor. J. Immunol. 141:1670.[Abstract]
  32. Nozawa, K., N. Kayagaki, Y. Tokano, H. Yagita, K. Okumura, H. Hasimoto. 1997. Soluble Fas (APO-1, CD95) and soluble Fas ligand in rheumatic diseases. Arthritis Rheum. 40:1126.[Medline]
  33. Tanaka, M., T. Suda, K. Haze, N. Nakamura, K. Sato, F. Kimura, K. Motoyoshi, M. Mizuki, S. Tagawa, S. Ohga, et al 1996. Fas ligand in human serum. Nature Med. 2:317.[Medline]
  34. Hasegawa, D., S. Kojima, E. Tatsumi, A. Hayakawa, Y. Kosaka, H. Nakamura, M. Sako, Y. Osugi, S. Nagata, K. Sano. 1998. Elevation of the serum Fas ligand in patients with hemophagocytic syndrome and Diamond-Blackfan anemia. Blood 91:2793.[Abstract/Free Full Text]
  35. Toyozaki, T., M. Hiroe, M. Tanaka, S. Nagata, H. Ohwada, F. Marumo. 1998. Levels of soluble Fas ligand in myocarditis. Am. J. Cardiol. 82:246.[Medline]
  36. Taieb, J., P. Mathurin, T. Poynard, M. Gougerot-Pocidalo, S. Chollet-Martin. 1998. Raised plasma soluble Fas and Fas-ligand in alcoholic liver disease. Lancet 351:1930.[Medline]
  37. Hashimoto, H., M. Tanaka, T. Suda, T. Tomita, K. Hayashida, E. Takeuchi, M. Kaneko, H. Takano, S. Nagata, T. Ochi. 1998. Soluble Fas ligand in the joints of patients with rheumatoid arthritis and osteoarthritis. Arthritis Rheum. 41:657.[Medline]



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 J. Leukoc. Biol.Home page
T. Sato, K. Iwabuchi, I. Nagaoka, Y. Adachi, N. Ohno, H. Tamura, K. Seyama, Y. Fukuchi, H. Nakayama, F. Yoshizaki, et al.
Induction of human neutrophil chemotaxis by Candida albicans-derived {beta}-1,6-long glycoside side-chain-branched {beta}-glucan
J. Leukoc. Biol., July 1, 2006; 80(1): 204 - 211.
[Abstract] [Full Text] [PDF]

Home page
 J. Immunol.Home page
R. Sharma, H. Bagavant, W. N. Jarjour, S.-S. J. Sung, and S.-T. Ju
The Role of Fas in the Immune System Biology of IL-2R{alpha} Knockout Mice: Interplay among Regulatory T Cells, Inflammation, Hemopoiesis, and Apoptosis
J. Immunol., August 1, 2005; 175(3): 1965 - 1973.
[Abstract] [Full Text] [PDF]

Home page
 J. Immunol.Home page
J. J. Lum, G. Bren, R. McClure, and A. D. Badley
Elimination of Senescent Neutrophils by TNF-Related Apotosis-Inducing Ligand
J. Immunol., July 15, 2005; 175(2): 1232 - 1238.
[Abstract] [Full Text] [PDF]

Home page
 IOVSHome page
M. Engelbert and M. S. Gilmore
Fas Ligand but Not Complement Is Critical for Control of Experimental Staphylococcus aureus Endophthalmitis
Invest. Ophthalmol. Vis. Sci., July 1, 2005; 46(7): 2479 - 2486.
[Abstract] [Full Text] [PDF]

Home page
 J. Cell Sci.Home page
T. S. Soderstrom, S. D. Nyberg, and J. E. Eriksson
CD95 capping is ROCK-dependent and dispensable for apoptosis
J. Cell Sci., May 15, 2005; 118(10): 2211 - 2223.
[Abstract] [Full Text] [PDF]

Home page
 BloodHome page
N. Askenasy, E. S. Yolcu, I. Yaniv, and H. Shirwan
Induction of tolerance using Fas ligand: a double-edged immunomodulator
Blood, February 15, 2005; 105(4): 1396 - 1404.
[Abstract] [Full Text] [PDF]

Home page
 BloodHome page
M. Giroux and F. Denis
CD1d-unrestricted human NKT cells release chemokines upon Fas engagement
Blood, January 15, 2005; 105(2): 703 - 710.
[Abstract] [Full Text] [PDF]

Home page
 Int ImmunolHome page
M. Umemura, T. Kawabe, K. Shudo, H. Kidoya, M. Fukui, M. Asano, Y. Iwakura, G. Matsuzaki, R. Imamura, and T. Suda
Involvement of IL-17 in Fas ligand-induced inflammation
Int. Immunol., August 1, 2004; 16(8): 1099 - 1108.
[Abstract] [Full Text] [PDF]

Home page
 CVIHome page
G. Matute-Bello, R. K. Winn, T. R. Martin, and W. C. Liles
Sustained Lipopolysaccharide-Induced Lung Inflammation in Mice Is Attenuated by Functional Deficiency of the Fas/Fas Ligand System
Clin. Vaccine Immunol., March 1, 2004; 11(2): 358 - 361.
[Abstract] [Full Text] [PDF]

Home page
 Biol. Reprod.Home page
D. R Balkundi, J. A Ziegler, J. F Watchko, C. Craven, and M. Trucco
Regulation of FasL/Fas in Human Trophoblasts: Possible Implications for Chorioamnionitis
Biol Reprod, August 1, 2003; 69(2): 718 - 724.
[Abstract] [Full Text] [PDF]

Home page
 J. Immunol.Home page
S. Hoves, S. W. Krause, D. Halbritter, H.-G. Zhang, J. D. Mountz, J. Scholmerich, and M. Fleck
Mature But Not Immature Fas Ligand (CD95L)-Transduced Human Monocyte-Derived Dendritic Cells Are Protected from Fas-Mediated Apoptosis and Can Be Used as Killer APC
J. Immunol., June 1, 2003; 170(11): 5406 - 5413.
[Abstract] [Full Text] [PDF]

Home page
 CirculationHome page
N. Askenasy, E. S. Yolcu, Z. Wang, and H. Shirwan
Display of Fas Ligand Protein on Cardiac Vasculature as a Novel Means of Regulating Allograft Rejection
Circulation, March 25, 2003; 107(11): 1525 - 1531.
[Abstract] [Full Text] [PDF]

Home page
 BloodHome page
S. Buonocore, F. Paulart, A. Le Moine, M. Braun, I. Salmon, S. Van Meirvenne, K. Thielemans, M. Goldman, and V. Flamand
Dendritic cells overexpressing CD95 (Fas) ligand elicit vigorous allospecific T-cell responses in vivo
Blood, February 15, 2003; 101(4): 1469 - 1476.
[Abstract] [Full Text] [PDF]

Home page
 J. Immunol.Home page
S. A. Renshaw, J. S. Parmar, V. Singleton, S. J. Rowe, D. H. Dockrell, S. K. Dower, C. D. Bingle, E. R. Chilvers, and M. K. B. Whyte
Acceleration of Human Neutrophil Apoptosis by TRAIL
J. Immunol., January 15, 2003; 170(2): 1027 - 1033.
[Abstract] [Full Text] [PDF]

Home page
 BloodHome page
K. Iwabuchi and I. Nagaoka
Lactosylceramide-enriched glycosphingolipid signaling domain mediates superoxide generation from human neutrophils
Blood, July 30, 2002; 100(4): 1454 - 1464.
[Abstract] [Full Text] [PDF]

Home page
 J. Leukoc. Biol.Home page
F. H. Igney and P. H. Krammer
Immune escape of tumors: apoptosis resistance and tumor counterattack
J. Leukoc. Biol., June 1, 2002; 71(6): 907 - 920.
[Abstract] [Full Text] [PDF]

Home page
 J Am Coll CardiolHome page
M. Shimizu, K. Fukuo, S. Nagata, T. Suhara, M. Okuro, K. Fujii, Y. Higashino, M. Mogi, Y. Hatanaka, and T. Ogihara
Increased plasma levels of the soluble form of fas ligand in patients with acute myocardial infarction and unstable angina pectoris
J. Am. Coll. Cardiol., February 20, 2002; 39(4): 585 - 590.
[Abstract] [Full Text] [PDF]

Home page
 J. Immunol.Home page
I. Monleon, M. J. Martinez-Lorenzo, L. Monteagudo, P. Lasierra, M. Taules, M. Iturralde, A. Pineiro, L. Larrad, M. A. Alava, J. Naval, et al.
Differential Secretion of Fas Ligand- or APO2 Ligand/TNF-Related Apoptosis-Inducing Ligand-Carrying Microvesicles During Activation-Induced Death of Human T Cells
J. Immunol., December 15, 2001; 167(12): 6736 - 6744.
[Abstract] [Full Text] [PDF]

Home page
 J. Immunol.Home page
A. M. Hohlbaum, M. S. Gregory, S.-T. Ju, and A. Marshak-Rothstein
Fas Ligand Engagement of Resident Peritoneal Macrophages In Vivo Induces Apoptosis and the Production of Neutrophil Chemotactic Factors
J. Immunol., December 1, 2001; 167(11): 6217 - 6224.
[Abstract] [Full Text] [PDF]

Home page
 BloodHome page
H. Matsue, K. Matsue, M. Kusuhara, T. Kumamoto, K. Okumura, H. Yagita, and A. Takashima
Immunosuppressive properties of CD95L-transduced "killer" hybrids created by fusing donor- and recipient-derived dendritic cells
Blood, December 1, 2001; 98(12): 3465 - 3472.
[Abstract] [Full Text] [PDF]

Home page
 JEMHome page
V. M. Borges, H. Falcao, J. H. Leite-Junior, L. Alvim, G. P. Teixeira, M. Russo, A. F. Nobrega, M. F. Lopes, P. M. Rocco, W. F. Davidson, et al.
FAS Ligand Triggers Pulmonary Silicosis
J. Exp. Med., July 16, 2001; 194(2): 155 - 164.
[Abstract] [Full Text] [PDF]

Home page
 Infect. Immun.Home page
F. H. Falcone, A. G. Rossi, R. Sharkey, A. P. Brown, D. I. Pritchard, and R. M. Maizels
Ascaris suum-Derived Products Induce Human Neutrophil Activation via a G Protein-Coupled Receptor That Interacts with the Interleukin-8 Receptor Pathway
Infect. Immun., June 1, 2001; 69(6): 4007 - 4018.
[Abstract] [Full Text] [PDF]

Home page
 JEMHome page
Y. Miura, N. Misawa, N. Maeda, Y. Inagaki, Y. Tanaka, M. Ito, N. Kayagaki, N. Yamamoto, H. Yagita, H. Mizusawa, et al.
Critical Contribution of Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand (Trail) to Apoptosis of Human Cd4+T Cells in HIV-1-Infected Hu-Pbl-Nod-Scid Mice
J. Exp. Med., March 5, 2001; 193(5): 651 - 660.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
W. Roth, S. Isenmann, M. Nakamura, M. Platten, W. Wick, P. Kleihues, M. Bähr, H. Ohgaki, A. Ashkenazi, and M. Weller
Soluble Decoy Receptor 3 Is Expressed by Malignant Gliomas and Suppresses CD95 Ligand-induced Apoptosis and Chemotaxis
Cancer Res., March 1, 2001; 61(6): 2759 - 2765.
[Abstract] [Full Text]

Home page
 J. Immunol.Home page
C. K. Behrens, F. H. Igney, B. Arnold, P. Moller, and P. H. Krammer
CD95 Ligand-Expressing Tumors Are Rejected in Anti-Tumor TCR Transgenic Perforin Knockout Mice
J. Immunol., March 1, 2001; 166(5): 3240 - 3247.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Pathol.Home page
G. Matute-Bello, R. K. Winn, M. Jonas, E. Y. Chi, T. R. Martin, and W. C. Liles
Fas (CD95) Induces Alveolar Epithelial Cell Apoptosis in Vivo : Implications for Acute Pulmonary Inflammation
Am. J. Pathol., January 1, 2001; 158(1): 153 - 161.
[Abstract] [Full Text] [PDF]

Home page
 J. Immunol.Home page
J. L. Wahlsten, H. L. Gitchell, C.-C. Chan, B. Wiggert, and R. R. Caspi
Fas and Fas Ligand Expressed on Cells of the Immune System, not on the Target Tissue, Control Induction of Experimental Autoimmune Uveitis
J. Immunol., November 15, 2000; 165(10): 5480 - 5486.
[Abstract] [Full Text] [PDF]

Home page
 J. Immunol.Home page
T. Waku, T. Fujiwara, J. Shao, T. Itoshima, T. Murakami, M. Kataoka, S. Gomi, J. A. Roth, and N. Tanaka
Contribution of CD95 Ligand-Induced Neutrophil Infiltration to the Bystander Effect in p53 Gene Therapy for Human Cancer
J. Immunol., November 15, 2000; 165(10): 5884 - 5890.
[Abstract] [Full Text] [PDF]

Home page
 JCBHome page
G. Le'Negrate, E. Selva, P. Auberger, B. Rossi, and P. Hofman
Sustained Polymorphonuclear Leukocyte Transmigration Induces Apoptosis in T84 Intestinal Epithelial Cells
J. Cell Biol., September 18, 2000; 150(6): 1479 - 1488.
[Abstract] [Full Text] [PDF]

Home page
 JEMHome page
A. Villunger, L. A. O'Reilly, N. Holler, J. Adams, and A. Strasser
FAS Ligand, Bcl-2, Granulocyte Colony-Stimulating Factor, and p38 Mitogen-Activated Protein Kinase: Regulators of Distinct Cell Death and Survival Pathways in Granulocytes
J. Exp. Med., September 5, 2000; 192(5): 647 - 658.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Respir. Crit. Care Med.Home page
K. AOSHIBA, S. YASUI, J. TAMAOKI, and A. NAGAI
The Fas/Fas-Ligand System Is Not Required for Bleomycin-induced Pulmonary Fibrosis in Mice
Am. J. Respir. Crit. Care Med., August 1, 2000; 162(2): 695 - 700.
[Abstract] [Full Text] [PDF]

Home page
 J. Am. Soc. Nephrol.Home page
C. LORZ, A. ORTIZ, P. JUSTO, S. GONZÁLEZ-CUADRADO, N. DUQUE, C. GÓMEZ-GUERRERO, and J. EGIDO
Proapoptotic Fas Ligand Is Expressed by Normal Kidney Tubular Epithelium and Injured Glomeruli
J. Am. Soc. Nephrol., July 1, 2000; 11(7): 1266 - 1277.
[Abstract] [Full Text]

Home page
 Am. J. Respir. Cell Mol. Bio.Home page
J.A. D. Cooper Jr.
Pulmonary Fibrosis . Pathways Are Slowly Coming into Light
Am. J. Respir. Cell Mol. Biol., May 1, 2000; 22(5): 520 - 523.
[Full Text]

Home page
 Am. J. Physiol. Regul. Integr. Comp. Physiol.Home page
M. D. Josephs, F. R. Bahjat, K. Fukuzuka, R. Ksontini, C. C. Solorzano, C. K. Edwards III, C. L. Tannahill, S. L. D. MacKay, E. M. Copeland III, and L. L. Moldawer
Lipopolysaccharide and D-galactosamine-induced hepatic injury is mediated by TNF-alpha and not by Fas ligand
Am J Physiol Regulatory Integrative Comp Physiol, May 1, 2000; 278(5): R1196 - R1201.
[Abstract] [Full Text] [PDF]

Home page
 JEMHome page
A. M. Hohlbaum, S. Moe, and A. Marshak-Rothstein
Opposing Effects of Transmembrane and Soluble FAS Ligand Expression on Inflammation and Tumor Cell Survival
J. Exp. Med., April 3, 2000; 191(7): 1209 - 1220.
[Abstract] [Full Text] [PDF]

Home page
 Nephrol Dial TransplantHome page
A. Ortiz, C. Lorz, and J. Egido
The Fas ligand/Fas system in renal injury
Nephrol. Dial. Transplant., August 1, 1999; 14(8): 1831 - 1834.
[Full Text] [PDF]

Home page
 J. Immunol.Home page
M. Shimizu, A. Fontana, Y. Takeda, H. Yagita, T. Yoshimoto, and A. Matsuzawa
Induction of Antitumor Immunity with Fas/APO-1 Ligand (CD95L)-Transfected Neuroblastoma Neuro-2a Cells
J. Immunol., June 15, 1999; 162(12): 7350 - 7357.
[Abstract] [Full Text] [PDF]

Home page
 J. Immunol.Home page
L. Ottonello, G. Tortolina, M. Amelotti, and F. Dallegri
Soluble Fas Ligand Is Chemotactic for Human Neutrophilic Polymorphonuclear Leukocytes
J. Immunol., March 15, 1999; 162(6): 3601 - 3606.
[Abstract] [Full Text] [PDF]

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