A Study on Tumor Necrosis Factor, Tumor Necrosis Factor Receptors, and Nitric Oxide in Human Fetal Glial Cultures

Barbara A.St Pierre, Douglas A. Granger, Joyce L. Wong, Jean E. Merrill

Research output: Contribution to journalArticle

9 Scopus citations

Abstract

This chapter presents the main novel findings concerning human fetal astrocyte tumor necrosis factor receptors (TNF-Rs) and nitric oxide (NO). The focus is on interleukin-1β (IL-1β) and Interferon-γ (IFN-γ) treatment that leads to increased soluble TNF-R concentrations in astrocyte supernatants without a detectable change in surface TNF-Rs, the inhibition of cytokine-induced soluble TNF-Rs by pentoxifylline (PTX); but it does not affect surface TNF-R, the association of elevated soluble TNF-R levels with increased TNF and NO production. It is concluded that during CNS inflammation, such as MS, NO production is accompanied by changes in TNF-Rs, which may either limit or prolong the effects that NO has on surrounding cells or invading pathogens. Indeed, NO concentrations may be regulated, in part, by modulating TNF-R shedding. Recent findings suggest that TNF effects on a target cell are mediated, in part, by the presence of soluble extracellular TNF receptor (TNF-R) fragments cleaved from intact surface receptors by proteases. These soluble TNF-Rs can bind to TNF and inhibit or prolong its activity, and are additional pathways by which TNF can be modulated. Thus, the maintenance of NO levels within a nonpathological range may depend not only on limiting inducible nitric oxide synthase (iNOS), but also on regulating cytokine pathways associated with iNOS activation. One of the aims of the chapter is to discuss the evidence of the production and regulation of TNF, TNF-Rs, and NO production in human glial cell cultures. These studies are based on the hypothesis that TNF, IL-1, and NO mediate demyelination in multiple sclerosis (MS) plaques and neuronal damage in acquired immunodeficiency syndrome (AIDS) dementia, both of which may contribute to the clinical manifestations of these conditions.

Original languageEnglish (US)
Pages (from-to)415-438
Number of pages24
JournalAdvances in Pharmacology
Volume34
Issue numberC
DOIs
StatePublished - Jan 1 1995

ASJC Scopus subject areas

  • Pharmacology

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