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The effect of non-steroidal anti-inflammatory drugs on IL-1 production

Bahl, Ashwani Kumar; (1992) The effect of non-steroidal anti-inflammatory drugs on IL-1 production. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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Abstract

The effect of non-steroidal anti-inflammatory drugs (NSAIDs) has been investigated on interleukin-1 (IL-1) production from resident murine macrophages. By the use of a more sensitive and selective bioassay than has previously been used, it was found that a variety of NSAIDs potentiated the secretion of IL-1 from lipopolysaccharide (LPS)-stimulated macrophages. However, high concentrations of NSAID were required (10 -5M or greater) and this effectcould be dissociated from cyclo- oxygenase inhibition. The effect of NSAIDs on cell-associated IL-1 was also investigated. NSAIDs dose-dependently increased the accumulation of IL-1 by LPS-stimulated macrophages. This effect was found to parallel cyclo- oxygenase inhibition and could dose-dependently be reversed by prostaglandin E2. Two selective 5-lipoxygenase inhibitors were without effect on IL-1 production from LPS-stimulated macrophages in the presence or absence of a NSAID. The ability of NSAIDs to affect IL-1 production by a range of receptor and post-receptor stimuli was tested. Contrary to published reports it was found that: 1). Certain neuropeptides were unable to stimulate IL-1 production 2). Tumour necrosis factor (TNF) and calcium ionophores only stimulated cell- associated IL-1 3). A phorbol ester was unable to stimulate IL-1 production. NSAIDs were unable to affect IL-1 production from TNF- or ionophore- stimulated macrophages, thus suggesting a mechanism specific to LPS was being affected. The ability of indomethacin to inhibit diglyceride metabolism was investigated as a possible mechanism contributing to enhanced IL-1 production. Indomethacin, unlike R59022 (a diacylglycerol kinase inhibitor) was without affect on dioctanoyl 1,2 (sn) glycerol-stimulated IL-1 production however, at 10 -5M both drugs potentiated IL-1 activation of EL4 NOBls (aT cell line). This study supports a rble for PGE2 as a downregulator of IL-1 production and shows' that NSAIDs can potentiate IL-1 production and action by mechanisms unrelated to cyclo-oxygenase inhibition.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: The effect of non-steroidal anti-inflammatory drugs on IL-1 production
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Thesis digitised by ProQuest.
URI: https://discovery.ucl.ac.uk/id/eprint/10123968
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