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Journal of Lipid Research, Vol. 45, 1482-1492, August 2004
Copyright © 2004 by American Society for Biochemistry and Molecular Biology

Dietary n-3 polyunsaturated fatty acids promote activation-induced cell death in Th1-polarized murine CD4⁺ T-cells

Kirsten C. Switzer^*, Yang-Yi Fan^*, Naisyin Wang, David N. McMurray^*,,** and Robert S. Chapkin^1,*,

^* Molecular and Cell Biology Section, Faculty of Nutrition, Texas A&M University, College Station, TX
Department of Statistics, Texas A&M University, College Station, TX
Center for Environmental and Rural Health, Texas A&M University, College Station, TX
^** Department of Microbiology and Immunology, Texas A&M University Health Science Center, College Station, TX

¹ To whom correspondence should be addressed. e-mail: r-chapkin{at}tamu.edu

Dietary n-3 PUFAs have been shown to attenuate T-cell-mediated inflammation. To investigate whether dietary n-3 PUFAs promote activation-induced cell death (AICD) in CD4⁺ T-cells induced in vitro to a polarized T-helper1 (Th1) phenotype, C57BL/6 mice were fed diets containing either 5% corn oil (CO; n-6 PUFA control) or 4% fish oil (FO) plus 1% CO (n-3 PUFA) for 2 weeks. Splenic CD4⁺ T-cells were cultured with -interleukin-4 (IL-4), IL-12, and IL-2 for 2 days and then with recombinant (r) IL-12 and rIL-2 for 3 days in the presence of diet-matched homologous mouse serum (HMS) to prevent loss of cell membrane fatty acids, or with fetal bovine serum. After polarization, Th1 cells were reactivated and analyzed for interferon- and IL-4 by intracellular cytokine staining and for apoptosis by Annexin V/propidium iodide. Dietary FO enhanced Th1 polarization by 49% (P = 0.0001) and AICD by 24% (P = 0.0001) only in cells cultured in the presence of HMS. FO enhancement of Th1 polarization and AICD after culture was associated with the maintenance of eicosapentaenoic acid (20:5n-3) and docosahexaenoic acid (22:6n-3) in plasma membrane lipid rafts.

In conclusion, n-3 PUFAs enhance the polarization and deletion of proinflammatory Th1 cells, possibly as a result of alterations in membrane microdomain fatty acid composition.

Abbreviations: AICD, activation-induced cell death; CO, corn oil; DHA, docosahexaenoic acid; DISC, death-inducing signaling complex; EPA, eicosapentaenoic acid; FADD, Fas-associated death domain; FO, fish oil; HMS, homologous mouse serum; IFNR, interferon- receptor; IL, interleukin; PGE₂, prostaglandin E₂; PI, propidium iodide; PMA, phorbol-12-myristate-13-acetate; PPAR, peroxisome proliferator-activated receptor; Th, T-helper; TNF-ß, tumor necrosis factor-ß

Supplementary key words docosahexaenoic acid • eicosapentaenoic acid • lipid rafts • interferon-

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