Effect of Dietary Fatty Acids on Inflammatory Gene Expression in Healthy Humans

Jonathan P. Arm,Michael Seeds,L. Douglas Case,Priscilla Ivester,Floyd H. Chilton,Kelly L. Weaver

doi:10.1074/jbc.m109.004861

Abstract

Over the past 100 years, changes in the food supply in Western nations have resulted in alterations in dietary fatty acid consumption, leading to a dramatic increase in the ratio of omega-6 (omega6) to omega3 polyunsaturated fatty acids (PUFA) in circulation and in tissues. Increased omega6/omega3 ratios are hypothesized to increase inflammatory mediator production, leading to higher incidence of inflammatory diseases, and may impact inflammatory gene expression. To determine the effect of reducing the omega6/omega3 ratio on expression of inflammatory pathway genes in mononuclear cells, healthy humans were placed on a controlled diet for 1 week, then given fish oil and borage oil for an additional 4 weeks. Serum and neutrophil fatty acid composition and ex vivo leukotriene B(4) production from stimulated neutrophils were measured at the start and end of the supplementation period and after a 2-week washout. RNA was isolated from mononuclear cells and expression of PI3K, Akt, NFkappaB, and inflammatory cytokines was measured by real-time PCR. A marked increase was seen in serum and neutrophil levels of long-chain omega3 PUFA concomitant with a reduction in the omega6/omega3 PUFA ratio (40%). The ex vivo capacity of stimulated neutrophils to produce leukotriene B(4) was decreased by 31%. Expression of PI3Kalpha and PI3Kgamma and the quantity of PI3Kalpha protein in mononuclear cells was reduced after supplementation, as was the expression of several proinflammatory cytokines. These data reveal that PUFA may exert their clinical effects via their capacity to regulate the expression of signal transduction genes and genes for proinflammatory cytokines.

Highlights

1P50AT0027820. 1 To whom correspondence should be addressed: Wake Forest University has been exacerbated by changes in livestock husbandry and feeding practices [3]
The most studied mechanisms center around the observation that shifts in dietary consumption of ␻6 and ␻3 polyunsaturated fatty acids (PUFA) lead to alterations in the quantities of ␻6 and ␻3-derived eicosanoids produced in animals and humans, thereby disturbing the balance of lipid-based pro- and antiinflammatory mediators produced at sites of inflammation
These experiments suggest that altering circulating levels of ␻6 and ␻3 PUFA likely influences inflammatory responses in part by the capacity of these fatty acids or their metabolites to regulate the expression of early signal transduction genes and to block the expression of pivotal cytokines and chemokines at a transcriptional level

Summary

Introduction

1P50AT0027820. 1 To whom correspondence should be addressed: Wake Forest University has been exacerbated by changes in livestock husbandry and feeding practices [3]. The current study has utilized a dietary intervention strategy in which healthy humans were fed controlled diets including dietary supplements containing specific dosages of short chain (18 carbon) PUFA and long chain (Ͼ20 carbon) PUFA in a manner, which is consistent with our understanding of early human diets These experiments suggest that altering circulating levels of ␻6 and ␻3 PUFA likely influences inflammatory responses in part by the capacity of these fatty acids or their metabolites to regulate the expression of early signal transduction genes and to block the expression of pivotal cytokines and chemokines at a transcriptional level

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