Author
Raymond J. Paxton
Other affiliations: Max Planck Society, University of North Carolina at Chapel Hill, City of Hope National Medical Center
Bio: Raymond J. Paxton is an academic researcher from Amgen. The author has contributed to research in topics: Carcinoembryonic antigen & Monoclonal antibody. The author has an hindex of 30, co-authored 53 publications receiving 8420 citations. Previous affiliations of Raymond J. Paxton include Max Planck Society & University of North Carolina at Chapel Hill.
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TL;DR: The results should facilitate the development of therapeutically useful inhibitors of TNF-α release, and they indicate that an important function of adamalysins may be to shed cell-surface proteins.
Abstract: Mammalian cells proteolytically release (shed) the extracellular domains of many cell-surface proteins. Modification of the cell surface in this way can alter the cell's responsiveness to its environment and release potent soluble regulatory factors. The release of soluble tumour-necrosis factor-alpha (TNF-alpha) from its membrane-bound precursor is one of the most intensively studied shedding events because this inflammatory cytokine is so physiologically important. The inhibition of TNF-alpha release (and many other shedding phenomena) by hydroxamic acid-based inhibitors indicates that one or more metalloproteinases is involved. We have now purified and cloned a metalloproteinase that specifically cleaves precursor TNF-alpha. Inactivation of the gene in mouse cells caused a marked decrease in soluble TNF-alpha production. This enzyme (called the TNF-alpha-converting enzyme, or TACE) is a new member of the family of mammalian adamalysins (or ADAMs), for which no physiological catalytic function has previously been identified. Our results should facilitate the development of therapeutically useful inhibitors of TNF-alpha release, and they indicate that an important function of adamalysins may be to shed cell-surface proteins.
3,007 citations
TL;DR: The phenotype of mice lacking TACE suggests an essential role for soluble TGFalpha in normal development and emphasizes the importance of protein ectodomain shedding in vivo.
Abstract: The ectodomains of numerous proteins are released from cells by proteolysis to yield soluble intercellular regulators. The responsible protease, tumor necrosis factor-alpha converting enzyme (TACE), has been identified only in the case when tumor necrosis factor-alpha (TNFalpha) is released. Analyses of cells lacking this metalloproteinase-disintegrin revealed an expanded role for TACE in the processing of other cell surface proteins, including a TNF receptor, the L-selectin adhesion molecule, and transforming growth factor-alpha (TGFalpha). The phenotype of mice lacking TACE suggests an essential role for soluble TGFalpha in normal development and emphasizes the importance of protein ectodomain shedding in vivo.
1,627 citations
Journal Article•
TL;DR: IL-15 has comparable activity with IL-2 for the induction of B cell proliferation and differentiation and uses at least some of the components of theIL-2R complex to mediate its effects.
Abstract: The identification and cloning of the novel cytokine IL-15 were recently described. IL-15 is produced by a wide range of cell types, with the highest levels of IL-15 mRNA being detected in epithelial lines, monocytes, muscle, and placenta. Although it has no sequence identity with IL-2, IL-15 shares many of the T cell-stimulatory activities described for IL-2. We have examined IL-15 for its ability to stimulate B cells and have compared its activity with that of IL-2. IL-15 costimulates proliferation of B cells activated with immobilized anti-human IgM or phorbol ester, but has no stimulatory effect on resting B cells. In combination with recombinant CD40L, IL-15 is a potent inducer of polyclonal IgM, IgG1, and IgA secretion, but does not cause production of IgG4 or IgE. The activity of IL-15 in B cell proliferation and differentiation assays is comparable with that of IL-2. Studies that used neutralizing Abs have demonstrated that, for signal transduction in B cells, IL-15 uses the beta-chain of the IL-2R complex but, unlike IL-2, does not require the alpha-chain. IL-2 is required for the generation of a human primary Ag-specific in vitro response using sheep erythrocytes as Ag. Of all cytokines examined, only IL-15 has the capacity to replace IL-2 in this system, although only partially. In summary, IL-15 has comparable activity with IL-2 for the induction of B cell proliferation and differentiation and uses at least some of the components of the IL-2R complex to mediate its effects.
445 citations
TL;DR: The data indicate that CSF1R signaling is required only for the maturation and replacement of resident-type monocytes and tissue macrophages, and is not required for monocyte production or inflammatory function.
433 citations
TL;DR: A broad role for TACE in the regulated shedding of EGFR ligands is supported, showing that cells lacking TACE activity shed dramatically less TGF-α as compared with wild-type cultures and that T GF-α cleavage was partially restored by infection of Tace-deficient cells with TACE-encoding adenovirus.
428 citations
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TL;DR: Atherosclerosis is an inflammatory disease as discussed by the authors, and it is a major cause of death in the United States, Europe, and much of Asia, despite changes in lifestyle and use of new pharmacologic approaches to lower plasma cholesterol concentrations.
Abstract: Atherosclerosis is an inflammatory disease. Because high plasma concentrations of cholesterol, in particular those of low-density lipoprotein (LDL) cholesterol, are one of the principal risk factors for atherosclerosis,1 the process of atherogenesis has been considered by many to consist largely of the accumulation of lipids within the artery wall; however, it is much more than that. Despite changes in lifestyle and the use of new pharmacologic approaches to lower plasma cholesterol concentrations,2,3 cardiovascular disease continues to be the principal cause of death in the United States, Europe, and much of Asia.4,5 In fact, the lesions of atherosclerosis represent . . .
19,881 citations
Journal Article•
TL;DR: Despite changes in lifestyle and the use of new pharmacologic approaches to lower plasma cholesterol concentrations, cardiovascular disease continues to be the principal cause of death in the United States, Europe, and much of Asia.
9,749 citations
TL;DR: It is shown that the MMPs have functions other than promotion of invasion, have substrates other than components of the extracellular matrix, and that they function before invasion in the development of cancer.
Abstract: Matrix metalloproteinases (MMPs) have long been associated with cancer-cell invasion and metastasis. This provided the rationale for clinical trials of MMP inhibitors, unfortunately with disappointing results. We now know, however, that the MMPs have functions other than promotion of invasion, have substrates other than components of the extracellular matrix, and that they function before invasion in the development of cancer. With this knowledge in hand, can we rethink the use of MMP inhibitors in the clinic?
5,860 citations
TL;DR: Recent advances shed light on how the structure and function of the MMPs are related and on how their transcription, secretion, activation, inhibition, localization, and clearance are controlled.
Abstract: ▪ Abstract The matrix metalloproteinases (MMPs) constitute a multigene family of over 25 secreted and cell surface enzymes that process or degrade numerous pericellular substrates. Their targets include other proteinases, proteinase inhibitors, clotting factors, chemotactic molecules, latent growth factors, growth factor–binding proteins, cell surface receptors, cell-cell adhesion molecules, and virtually all structural extracellular matrix proteins. Thus MMPs are able to regulate many biologic processes and are closely regulated themselves. We review recent advances that help to explain how MMPs work, how they are controlled, and how they influence biologic behavior. These advances shed light on how the structure and function of the MMPs are related and on how their transcription, secretion, activation, inhibition, localization, and clearance are controlled. MMPs participate in numerous normal and abnormal processes, and there are new insights into the key substrates and mechanisms responsible for regula...
3,839 citations
TL;DR: The authors regret the inability to cite all of the primary literature contributing to this review due to length considerations, but wish to thank F. Chan, T. Migone, and J. Wang for insightful comments on the manuscript.
3,756 citations