Walker R. Force

Bio: Walker R. Force is an academic researcher from University of California, Riverside. The author has contributed to research in topics: Lymphotoxin beta receptor & Lymphotoxin. The author has an hindex of 10, co-authored 12 publications receiving 2001 citations. Previous affiliations of Walker R. Force include La Jolla Institute for Allergy and Immunology.

Cell-autonomous Fas (CD95)/Fas-ligand interaction mediates activation-induced apoptosis in T-cell hybridomas

Abstract: A number of murine T-cell hybridomas undergo apoptosis within a few hours of activation by specific antigens, mitogens, antibodies against the T-cell antigen receptor, or a combination of phorbol ester and calcium ionophore. This phenomenon has been extensively studied as a model for clonal deletion in the immune system, in which potentially autoreactive T cells eliminate themselves by apoptosis after activation, either in the thymus or in the periphery. Here we show that the Fas/CD95 receptor, which can transduce a potent apoptotic signal when ligand, is rapidly expressed following activation of T-cell hybridomas, as is its functional, membrane-bound ligand. Interference with the ensuing Fas/Fas-ligand interaction inhibits activation-induced apoptosis. Because T-cell receptor ligation can induce apoptosis in a single T hybridoma cell, we suggest that the Fas/Fas-ligand interaction can induce cell death in a cell-autonomous manner.

Lymphotoxin-β receptor signaling complex: Role of tumor necrosis factor receptor-associated factor 3 recruitment in cell death and activation of nuclear factor κB

Abstract: The binding of heterotrimeric lymphotoxin, LTα1β2, to the LTβ receptor (LTβR), a member of the tumor necrosis factor receptor (TNFR) superfamily, induces nuclear factor κB (NF-κB) activation and cell death in HT29 adenocarcinoma cells. We now show that treatment with LTα1β2 or agonistic LTβR antibodies causes rapid recruitment of TNFR-associated factor 3 (TRAF3) to the LTβR cytoplasmic domain. Further, stable overexpression of a TRAF3 mutant that lacks the RING and zinc finger domains inhibits LTβR-mediated cell death. The inhibition is specific for LTβR cell death signaling, since NF-κB activation by LTα1β2 and Fas-mediated apoptosis are not inhibited in the same cells. The mutant and endogenous TRAF3s are both recruited at equimolar amounts to the LTβR, suggesting that the mutant disrupts the function of the signaling complex. These results implicate TRAF3 as a critical component of the LTβR death signaling complex and indicate that at least two independent signaling pathways are initiated by LTβR ligation.

Anti-CD40 monoclonal antibody

Abstract: An antibody or a functional fragment thereof, acting agonistically or antagonistically on CD40.

Mouse lymphotoxin-beta receptor. Molecular genetics, ligand binding, and expression.

Abstract: Lymphotoxin (LT) -alpha beta heterotrimer is a membrane-anchored ligand expressed by activated T cells which binds specifically to the LT beta receptor (LT beta R), a member of the TNFR family. The LT beta R is implicated as a critical element in controlling lymph node development and cellular immune reactions. To address this hypothesis we have isolated a mouse cDNA encoding a single transmembrane protein of 415 amino acids with 76% identity to human LT beta R. The receptor function of this molecule was demonstrated by the ability of the extracellular domain, constructed as a chimera with the Fc region of IgG7, to bind to LT alpha beta complexes expressed on the surface of activated T cells or insect cells infected with baculoviruses containing LT alpha and LT beta cDNAs. The gene encoding mouse LT beta R, Ltbr, contains 10 exons spanning 6.9 kb and maps to mouse chromosome 6, which is closely linked to Tnfr1, consistent with the tight linkage of the human homologue of these genes on chromosome 12p13. Mouse LT beta R mRNA is expressed by cell lines of monocytic and epithelial origin but not by a CTL line, and in vivo it is constitutively expressed in visceral and lymphoid tissues. The delineation of the structure of the mouse LT beta R will aid investigations into the role of this cytokine-receptor system in immune function and development.

Early redistribution of plasma membrane phosphatidylserine is a general feature of apoptosis regardless of the initiating stimulus: inhibition by overexpression of Bcl-2 and Abl.

Abstract: A critical event during programmed cell death (PCD) appears to be the acquisition of plasma membrane (PM) changes that allows phagocytes to recognize and engulf these cells before they rupture. The majority of PCD seen in higher organisms exhibits strikingly similar morphological features, and this form of PCD has been termed apoptosis. The nature of the PM changes that occur on apoptotic cells remains poorly defined. In this study, we have used a phosphatidylserine (PS)-binding protein (annexin V) as a specific probe to detect redistribution of this phospholipid, which is normally confined to the inner PM leaflet, during apoptosis. Here we show that PS externalization is an early and widespread event during apoptosis of a variety of murine and human cell types, regardless of the initiating stimulus, and precedes several other events normally associated with this mode of cell death. We also report that, under conditions in which the morphological features of apoptosis were prevented (macromolecular synthesis inhibition, overexpression of Bcl-2 or Abl), the appearance of PS on the external leaflet of the PM was similarly prevented. These data are compatible with the notion that activation of an inside-outside PS translocase is an early and widespread event during apoptosis.

Tumoricidal activity of tumor necrosis factor-related apoptosis-inducing ligand in vivo

Abstract: To evaluate the utility of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) as a cancer therapeutic, we created leucine zipper (LZ) forms of human (hu) and murine (mu) TRAIL to promote and stabilize the formation of trimers. Both were biologically active, inducing apoptosis of both human and murine target cells in vitro with similar specific activities. In contrast to the fulminant hepatotoxicity of LZ-huCD95L in vivo, administration of either LZ-huTRAIL or LZ-muTRAIL did not seem toxic to normal tissues of mice. Finally, repeated treatments with LZ-huTRAIL actively suppressed growth of the TRAIL-sensitive human mammary adenocarcinoma cell line MDA-231 in CB.17 (SCID) mice, and histologic examination of tumors from SCID mice treated with LZ-huTRAIL demonstrated clear areas of apoptotic necrosis within 9-12 hours of injection.

Fas Ligand-Induced Apoptosis as a Mechanism of Immune Privilege

Abstract: The eye is a privileged site that cannot tolerate destructive inflammatory responses. Inflammatory cells entering the anterior chamber of the eye in response to viral infection underwent apoptosis that was dependent on Fas (CD95)-Fas ligand (FasL) and produced no tissue damage. In contrast, viral infection in gld mice, which lack functional FasL, resulted in an inflammation and invasion of ocular tissue without apoptosis. Fas-positive but not Fas-negative tumor cells were killed by apoptosis when placed within isolated anterior segments of the eyes of normal but not FasL-negative mice. FasL messenger RNA and protein were detectable in the eye. Thus, Fas-FasL interactions appear to be an important mechanism for the maintenance of immune privilege.

Physiological and molecular basis of thyroid hormone action.

Abstract: Thyroid hormones (THs) play critical roles in the differentiation, growth, metabolism, and physiological function of virtually all tissues. TH binds to receptors that are ligand-regulatable transcription factors belonging to the nuclear hormone receptor superfamily. Tremendous progress has been made recently in our understanding of the molecular mechanisms that underlie TH action. In this review, we present the major advances in our knowledge of the molecular mechanisms of TH action and their implications for TH action in specific tissues, resistance to thyroid hormone syndrome, and genetically engineered mouse models.