Tumor necrosis factor-alpha (TNF-alpha) is critically involved in a wide variety of inflammatory pathologies, such as hepatitis, via the TNF receptor-1 (TNFR1). To develop TNFR1-targeted anti-inflammatory drugs, we have already succeeded in creating a TNFR1-selective antagonistic mutant TNF-alpha (R1antTNF) and shown that R1antTNF efficiently inhibits TNF-alpha/TNFR1-mediated biological activity in vitro. In this study, we examined the therapeutic effect of R1antTNF in acute hepatitis using two independent experimental models, induced by carbon tetrachloride (CCl(4)) or concanavalin A (ConA). In a CCl(4)-induced model, treatment with R1antTNF significantly inhibited elevation in the serum level of ALT (alanine aminotransferase), a marker for liver damage. In a ConA-induced T-cell-mediated hepatitis model, R1antTNF also inhibited the production of serum immune activated markers such as IL-2 and IL-6. These R1antTNF-mediated therapeutic effects were as good as or better than those obtained using conventional anti-TNF-alpha antibody therapy. Our results suggest that R1antTNF may be a clinically useful TNF-alpha antagonist in hepatitis.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.1016/j.cyto.2008.07.003 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Co-modulation of TNFR1 and TNFR2 in an animal model of multiple sclerosis.
J Neuroinflammation
April 2023
Department of Neurology, University Clinic Heidelberg, University of Heidelberg, Otto-Mayerhof-Zentrum (OMZ), Im Neuenheimer Feld 350, 69120, Heidelberg, Germany.
Background: Tumour necrosis factor (TNF) is a pleiotropic cytokine and master regulator of the immune system. It acts through two receptors resulting in often opposing biological effects, which may explain the lack of therapeutic potential obtained so far in multiple sclerosis (MS) with non-receptor-specific anti-TNF therapeutics. Under neuroinflammatory conditions, such as MS, TNF receptor-1 (TNFR1) is believed to mediate the pro-inflammatory activities associated with TNF, whereas TNF receptor-2 (TNFR2) may instead induce anti-inflammatory effects as well as promote remyelination and neuroprotection.
View Article and Find Full Text PDFStructural optimization of a TNFR1-selective antagonistic TNFα mutant to create new-modality TNF-regulating biologics.
J Biol Chem
July 2020
Laboratory of Cellular and Molecular Physiology, The Faculty of Pharmaceutical Sciences, Kobe Gakuin University, Chuo-ku, Kobe, Japan
Excessive activation of the proinflammatory cytokine tumor necrosis factor-α (TNFα) is a major cause of autoimmune diseases, including rheumatoid arthritis. TNFα induces immune responses via TNF receptor 1 (TNFR1) and TNFR2. Signaling via TNFR1 induces proinflammatory responses, whereas TNFR2 signaling is suggested to suppress the pathophysiology of inflammatory diseases.
View Article and Find Full Text PDFA trimeric structural fusion of an antagonistic tumor necrosis factor-α mutant enhances molecular stability and enables facile modification.
J Biol Chem
April 2017
From the Laboratory of Biopharmaceutical Research and
Tumor necrosis factor-α (TNF) exerts its biological effect through two types of receptors, p55 TNF receptor (TNFR1) and p75 TNF receptor (TNFR2). An inflammatory response is known to be induced mainly by TNFR1, whereas an anti-inflammatory reaction is thought to be mediated by TNFR2 in some autoimmune diseases. We have been investigating the use of an antagonistic TNF mutant (TNFR1-selective antagonistic TNF mutant (R1antTNF)) to reveal the pharmacological effect of TNFR1-selective inhibition as a new therapeutic modality.
View Article and Find Full Text PDFEssential protective role of tumor necrosis factor receptor 2 in neurodegeneration.
Proc Natl Acad Sci U S A
October 2016
Department of Molecular Neurobiology, Groningen Institute of Evolutionary Life Sciences, Faculty of Mathematics and Natural Sciences, University of Groningen, NL-9700 CC Groningen, The Netherlands; Department of Psychiatry, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
Despite the recognized role of tumor necrosis factor (TNF) in inflammation and neuronal degeneration, anti-TNF therapeutics failed to treat neurodegenerative diseases. Animal disease models had revealed the antithetic effects of the two TNF receptors (TNFR) in the central nervous system, whereby TNFR1 has been associated with inflammatory degeneration and TNFR2 with neuroprotection. We here show the therapeutic potential of selective inhibition of TNFR1 and activation of TNFR2 by ATROSAB, a TNFR1-selective antagonistic antibody, and EHD2-scTNF, an agonistic TNFR2-selective TNF, respectively, in a mouse model of NMDA-induced acute neurodegeneration.
View Article and Find Full Text PDFDevelopment of novel drug delivery systems using phage display technology for clinical application of protein drugs.
Proc Jpn Acad Ser B Phys Biol Sci
March 2017
Laboratory of Toxicology and Safety Science, Graduate School of Pharmaceutical Sciences, Osaka University.
Attempts are being made to develop therapeutic proteins for cancer, hepatitis, and autoimmune conditions, but their clinical applications are limited, except in the cases of drugs based on erythropoietin, granulocyte colony-stimulating factor, interferon-alpha, and antibodies, owing to problems with fundamental technologies for protein drug discovery. It is difficult to identify proteins useful as therapeutic seeds or targets. Another problem in using bioactive proteins is pleiotropic actions through receptors, making it hard to elicit desired effects without side effects.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!