The tumor necrosis factor (TNF) superfamily of cytokines includes both soluble and membrane-bound proteins that regulate immune responses. A member of the human TNF family, BLyS (B lymphocyte stimulator), was identified that induced B cell proliferation and immunoglobulin secretion. BLyS expression on human monocytes could be up-regulated by interferon-gamma. Soluble BLyS functioned as a potent B cell growth factor in costimulation assays. Administration of soluble recombinant BLyS to mice disrupted splenic B and T cell zones and resulted in elevated serum immunoglobulin concentrations. The B cell tropism of BLyS is consistent with its receptor expression on B-lineage cells. The biological profile of BLyS suggests it is involved in monocyte-driven B cell activation.
High throughput cDNA sequencing has led to the identification of interferon-, a novel subclass of type I interferon that displays ϳ30% homology to other family members. Interferon-consists of 207 amino acids, including a 27-amino acid signal peptide and a series of cysteines conserved in type I interferons. The gene encoding interferon-is located on the short arm of chromosome 9 adjacent to the type I interferon gene cluster and is selectively expressed in epidermal keratinocytes. Expression of interferon-is significantly enhanced in keratinocytes upon viral infection, upon exposure to double-stranded RNA, or upon treatment with either interferon-␥ or interferon-. Administration of interferon-recombinant protein imparts cellular protection against viral infection in a species-specific manner. Interferon-activates the interferon-stimulated response element signaling pathway and a panel of genes similar to those regulated by other type I interferons including anti-viral mediators and transcriptional regulators. An antibody that neutralizes the type I interferon receptor completely blocks interferon-signaling, demonstrating that interferon-utilizes the same receptor as other type I interferons. Interferon-therefore defines a novel subclass of type I interferon that is expressed in keratinocytes and expands the repertoire of known proteins mediating host defense. Interferons (IFNs)1 are a family of functionally related cytokines that confer a range of cellular responses including antiviral, antiproliferative, antitumor, and immunomodulatory activities (1, 2). They are classified as type I or type II according to their structural and functional properties. Although the sole member of the type II family is IFN-␥, there are multiple members of the type I interferon class, which is divided into the IFN-␣, IFN-, and IFN-subclasses (1, 2). In humans, excluding psuedogenes, there are 13 non-allelic IFN-␣ genes, a single  gene, and a single gene. Members of the IFN-␣ family display greater than 80% identity to each other, IFN-displays ϳ60% identity to IFN-␣, and IFN- is ϳ40% identical to the other family members. The evolutionary conservation of the type I IFN genes is reflected in their common intron-less structure and their co-localization to the short arm of chromosome 9, which suggest that type I IFNs arose by gene duplication (3). The subtypes were initially categorized further by their cell of origin. IFN-␣ and IFN-genes were thought to be produced predominantly by leukocytes and IFN- by fibroblasts. However, upon appropriate induction, most human cell types can generate type I IFNs (2). Exposure to a variety of agents triggers the rapid and transient production of type I IFNs, with viruses being the most efficient natural inducers (4, 5). Certain bacteria can also induce expression, as can double-stranded RNA (dsRNA) and endotoxin. In contrast, trophoblast IFNs or IFN-, which are found only in ruminant ungulate species, are not induced by viral challenge (6). These genes are expressed by the embryonic trophoecto...
Successive rational mutations of human butyrylcholinesterase (BChE) followed by fusion to human serum albumin have yielded an efficient hydrolase that offers realistic options for therapy of cocaine overdose and abuse. This albumin-BChE prevented seizures in rats given a normally lethal cocaine injection (100 mg/kg, i.p.), lowered brain cocaine levels even when administered after the drug, and provided rescue after convulsions commenced. Moreover, it selectively blocked cocaine-induced reinstatement of drug seeking in rats that had previously self-administered cocaine. The enzyme treatment was well tolerated and may be worth exploring for clinical application in humans.
We also demonstrate that TACI interacts with nanomolar affinity with the BLyS-related tumor necrosis factor homologue APRIL for which no clear in vivo role has been described. BLyS and APRIL are capable of signaling through TACI to mediate NF-B responses in HEK293 cells. We conclude that TACI is a receptor for BLyS and APRIL and discuss the implications for B-cell biology.Members of the tumor necrosis factor superfamily of cytokines play diverse roles in the regulation of cell proliferation, differentiation, and survival. Notably, several members of this family play key roles in the regulation of the immune system (1). We and others have previously identified a novel TNF 1 -related ligand, BLyS (also known as BAFF, TALL-1, THANK, TNFSF20, and zTNF4) which is expressed on monocytes and induces B-cell proliferation and immunoglobulin secretion in vitro and in vivo (2-6). Like many members of the TNF family, BLyS has activity in vitro as a 152-amino acid soluble molecule and as a 258-amino acid transmembrane form (3). However, the biological significance of these two forms and their relative contributions in vivo remain to be resolved. More recently, transgenic mice that ectopically overexpress BLyS were shown to develop autoimmune-like phenotypes reminiscent of those observed in systemic lupus erythematosus (7-9). These findings suggest that BLyS plays an important role in the regulation of B-cell growth and humoral immunity.In order to understand the precise mechanism by which BLyS activates B-cells, the range of cell types BLyS may affect, and the potential role of BLyS as a therapeutic agent or target, we have used expression cloning to identify the receptor for BLyS. We have identified the orphan receptor TACI (10), previously characterized as being present on B-cells and a subset of T-cells, as the receptor for BLyS and show that this receptor is capable of mediating NF-B signaling in response to ligand binding. We also show that TACI interacts with another TNF family member, APRIL, which is closely related to BLyS. Parallel work by others has recently shown that TACI and a second TNFR family member, BCMA, are BLyS receptors (9, 11-14). EXPERIMENTAL PROCEDURESCell Culture and Media-HEK293T cells were cultured in Dulbecco's modified Eagle's medium (DMEM) containing 10% fetal bovine serum and transfected using LipofectAMINE Plus (Life Technologies, Gaithersburg, MD) according to the manufacturer's protocol. For expression cloning screens, cells were attached to plates with poly-D-lysine.Flow Cytometry-Cells were stained with monoclonal antibodies raised against BLyS at the indicated protein concentrations, with biotinylated BLyS as described previously (2), with recombinant TACI-Fc fusion protein or with recombinant Flag-tagged proteins which were subsequently detected by the M2 anti-Flag monoclonal antibody (Sigma). Flow cytometry was performed using a FACScan instrument and associated CellQuest software (Becton Dickinson, San Jose, CA).Library Preparation, Screening, and Other DNA Manipulations-All common DNA...
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