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Title:Modulation of macrophage tumor necrosis factor-alpha production by omega-3 polyunsaturated fatty acids, eicosanoids, and calcium
Author(s):Chen, Steven Enchi
Doctoral Committee Chair(s):Erdman, John W.
Department / Program:Food Science and Human Nutrition
Discipline:Food Science and Human Nutrition
Degree Granting Institution:University of Illinois at Urbana-Champaign
Degree:Ph.D.
Genre:Dissertation
Subject(s):Agriculture, Food Science and Technology
Health Sciences, Immunology
Abstract:This research was undertaken to investigate the suppression of tumor necrosis factor-$\alpha$ (TNF-$\alpha)$ production imparted by $\omega$-3 fatty acid (FA) enhancement on macrophage (m$\phi).$ In an in vitro system, murine monocytic cell lines and peritoneal m$\phi$ were incubated with either eicosapentaenoate-BSA (EPA, $\omega$-3), arachidonate-BSA (ARA, $\omega$-6), palmitoleate-BSA (PMOA, $\omega$-7), or BSA. EPA consistently caused $>$60% suppression of LPS-induced TNF-$\alpha$ synthesis. PMOA and BSA had no effect. Recombinant murine interferon-$\gamma$ (rMulFN-$\gamma)$ enhanced lipopolysaccharide (LPS)-induced TNF-$\alpha$ production and dose-dependently reduced the suppression caused by EPA. Indomethacin augmented TNF-$\alpha$ production; however, it did not completely abrogate the EPA-induced suppression. ARA caused suppression similar to EPA, but this was totally abrogated by indomethacin. The Ca$\sp{2+}$ ionophore ionomycin was effective as a priming agent and abrogated the EPA-induced suppression when used with LPS.
Eicosanoids derived from ARA (PGE$\sb2)$ and EPA (PGE$\sb3)$ are structurally different. Both PGE$\sb2$ and PGE$\sb3$ dose-dependently suppressed TNF-$\alpha.$ Their efficacy was dependent on concentration and the level of m$\phi$ stimulation, in the absence or presence of indomethacin.
TNF-$\alpha$ mRNA levels of control and EPA-enhanced groups were compared. When IFN-$\gamma$ was used, the mRNA levels of EPA-treated groups were equal in magnitude to the control groups'. Therefore, the observed suppression at the cellular level could not be attributed to differential levels of mRNA accumulation at low activational states. When ionomycin was used as a priming agent, the mRNA levels for the EPA group was consistently higher than that of the controls', which, at the cellular level, was paralleled with abrogation of the differences in TNF-$\alpha$ detected between groups. Together, the findings suggested that post-transcriptional processes were responsible for the observed suppression of TNF-$\alpha.$
From these findings, $\omega$-3 FA enhancement of murine m$\phi$-induced suppression of TNF-$\alpha$ by a minimum of two paths. First, PGE$\sb3$ derived from EPA could directly cause suppression of TNF-$\alpha.$ Second, ionomycin, IFN-$\gamma$ and PKc activation demonstrated that up-regulation of this pathway could reverse the effects of $\omega$-3 FA enhancement.
Issue Date:1993
Type:Text
Language:English
URI:http://hdl.handle.net/2142/21361
Rights Information:Copyright 1993 Chen, Steven Enchi
Date Available in IDEALS:2011-05-07
Identifier in Online Catalog:AAI9411584
OCLC Identifier:(UMI)AAI9411584


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