EPA and DHA differentially modulate monocyte inflammatory response in subjects with chronic inflammation in part via plasma specialized pro-resolving lipid mediators: A randomized, double-blind, crossover study

Authors: SO, JISUN - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; WU, DAYONG - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; LICHTENSTEIN, ALICE - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; TAI, ALBERT - Tufts University; MATTHAN, NIRUPA - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; RAO MADDIPATI, KRISHAN - Wayne State University; LAMON-FAVA, STEFANIA - Jean Mayer Human Nutrition Research Center On Aging At Tufts University

Submitted to: Atherosclerosis
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 11/18/2020
Publication Date: 12/7/2020
Citation: So, J., Wu, D., Lichtenstein, A.H., Tai, A.K., Matthan, N.R., Rao Maddipati, K., Lamon-Fava, S. 2020. EPA and DHA differentially modulate monocyte inflammatory response in subjects with chronic inflammation in part via plasma specialized pro-resolving lipid mediators: A randomized, double-blind, crossover study. Atherosclerosis. 316:90-98. https://doi.org/10.1016/j.atherosclerosis.2020.11.018.
DOI: https://doi.org/10.1016/j.atherosclerosis.2020.11.018

Interpretive Summary: Inflammation is the primary defense of our organism against injury, bacteria and viruses. Chronic inflammation is typically associated with obesity, diabetes and cardiovascular disease. Two omega-3 fatty acids found in fish and fish oil, EPA and DHA, may reduce inflammation but it is not known if they work in a similar way. After ingestion, EPA and DHA are converted into several different molecules called pro-resolving lipid mediators (SPMs) that have been shown to promote the resolution of inflammation and thus prevent chronic inflammation. Our study was conducted in 21 middle-aged and older men and women with chronic inflammation. All subjects took capsules containing 3 g EPA per day for 10 weeks and 3 g DHA per day for 10 weeks in a random order. During treatment with EPA, subjects showed a modest reduction in inflammation and, during treatment with DHA, they showed a more pronounced reduction in inflammation but also a reduction in anti-inflammatory molecules. In addition, the blood levels of SPMs derived from EPA, but not DHA, were much better predictors of the activity of inflammatory molecules. Taken together, these results lead us to conclude that EPA has broader roles than DHA in reducing inflammation.

Technical Abstract: The independent effects of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) on chronic inflammation through their downstream lipid mediators, including the specialized pro-resolving lipid mediators (SPM), remain unstudied. Therefore, we compared the effects of EPA and DHA supplementation on monocyte inflammatory response and plasma polyunsaturated fatty acids (PUFA) SPM lipidome. Methods. After a 4-week lead-in phase (baseline), 9 men and 12 postmenopausal women (50-75 years) with chronic inflammation received two phases of 10-week supplementation with 3 g/day EPA and DHA in a random order, separated by a 10-week washout. Results. Compared with baseline, EPA and DHA supplementation differently modulated LPS-stimulated monocyte cytokine expression. EPA lowered TNFA (p < 0.001) whereas DHA reduced TNFA (p < 0.001), IL6 (p < 0.02), MCP1 (p < 0.03), and IL10 (p < 0.01). DHA lowered IL10 expression relative to EPA (p = 0.03). Relative to baseline, EPA, but not DHA, decreased the ratios of TNFA/IL10 and MCP1/IL10 (both p < 0.01). EPA and DHA also significantly changed plasma PUFA SPM lipidome by replacing n-6 AA derivatives with their respective derivatives including 18-hydroxy-EPA (+5 fold by EPA) and 17- and 14-hydroxy-DHA (+3 folds by DHA). However, DHA showed a wider effect than EPA by also significantly increasing EPA derivatives and DPA-derived SPM at a greater expense of AA derivatives. Different groups of PUFA derivatives mediated the differential effects of EPA and DHA on monocyte cytokine expression. Conclusions. EPA and DHA had distinct effects on monocyte inflammatory response with a broader effect of DHA in attenuating pro-inflammatory cytokines. These differential effects were potentially mediated by different groups of PUFA derivatives, suggesting immunomodulatory activities of SPM and their intermediates.