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The 60 kDa tumor necrosis factor receptor (TNFR60) is regarded as the major signal transducer of TNF-induced cellular responses, whereas the signal capacity and role of the 80 kDa TNFR (TNFR80) remain largely undefined. We show here that the transmembrane form of TNF is superior to soluble TNF in activating TNFR80 in various systems such as T cell(More)
The significance of tumor necrosis factor receptor 1 (TNFR1) for TNF function in vivo is well documented, whereas the role of TNFR2 so far remains obscure. In a model of concanavalin A (Con A)-induced, CD4+ T cell-dependent experimental hepatitis in mice, in which TNF is a central mediator of apoptotic and necrotic liver damage, we now provide evidence for(More)
Receptor activator of nuclear factor-κB ligand (RANKL), a trimeric tumor necrosis factor (TNF) superfamily member, is the central mediator of osteoclast formation and bone resorption. Functional mutations in RANKL lead to human autosomal recessive osteopetrosis (ARO), whereas RANKL overexpression has been implicated in the pathogenesis of bone degenerative(More)
The specific role of the tumor necrosis factor (TNF)/TNF receptor (TNFR) system in disease pathogenesis still remains an unresolved puzzle. Recent studies in transgenic and knockout animals, where the pathogenic influence of genetically perturbed TNF expression has been evaluated, indicate that several pathways of TNF/TNFR action may contribute(More)
Using targeted mutagenesis in mice, we have blocked shedding of endogenous murine TNF by deleting its cleavage site. Mutant mice produce physiologically regulated levels of transmembrane TNF (tmTNF), which suffice to support thymocyte proliferation but cannot substitute for the hepatotoxic activities of wild-type TNF following LPS/D-galactosamine challenge(More)
There is now good evidence to demonstrate that aberrations in tumour necrosis factor (TNF) production in vivo may be either pathogenic or protective and several plausible mechanisms may explain these contrasting activities. According to the classic pro-inflammatory scenario, failure to regulate the production of TNF at a site of immunological injury may(More)
Despite overwhelming evidence that enhanced production of the p75 tumor necrosis factor receptor (p75TNF-R) accompanies development of specific human inflammatory pathologies such as multi-organ failure during sepsis, inflammatory liver disease, pancreatitis, respiratory distress syndrome, or AIDS, the function of this receptor remains poorly defined in(More)
Transgenic mutagenesis in whole animals has become without doubt the most rewarding approach to analyse gene structure, expression, and function. In the TNF field, much of what we now question about TNF/TNF receptor function is based, to a large extent, on what we have already learned by overexpressing these molecules in transgenic mice or by ablating their(More)
Receptor activator of NF-κB ligand (RANKL) plays a key role in osteoclast-induced bone resorption across a range of degenerative bone diseases, and its specific inhibition has been recently approved as a treatment for women with postmenopausal osteoporosis at high or increased risk of fracture in the United States and globally. In the present study, we(More)
With the exponential increase in the number of genes identified by various genome projects, it has become imperative that efficient methods be developed for deciphering gene function. Genetically engineered strains of mice are now critical research tools for basic biomedical research and for genomic approaches for the development of new therapeutic(More)