Trebble TM, Arden NK, Wootton SA et al. Fish oil and antioxidants alter the composition and function of circulating mononuclear cells in Crohn disease. Am J Clinical Nutrition, 2004; 80 (5):1137-1144.

Background:
Crohn disease (CD) is associated with osteoporosis and other extraintestinal manifestations that might be mediated by cytokines from circulating (peripheral blood) mononuclear cells (PBMCs).
Fish oil rich in eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) reduces disease activity in patients with CD with raised laboratory markers of inflammation and in healthy subjects alters PBMC function.

Objective:
We investigated the effect of fish oil plus antioxidants on cytokine production by PBMCs from patients with CD with raised C-reactive protein concentrations (6.9 mg/L) or erythrocyte sedimentation rates (18 mm/h).

Design:
A randomized placebo-controlled trial of fish oil (2.7 g EPA and DHA/d; n = 31) or placebo (olive oil; n = 31) for 24 wk was conducted in patients with CD. The fish-oil group additionally received an antioxidant preparation (vitamins A, C, and E and selenium).
Exclusion criteria included corticosteroid use. Fatty acid composition was measured by gas chromatography.
Production of tumor necrosis factor , interferon (IFN-gamma), and prostaglandin E2 (PGE2) was measured by enzyme-linked immunosorbent assays after stimulation with mitogen and endotoxin (lipopolysaccharide).

Results:
Fish-oil plus antioxidant dietary supplementation was associated with higher EPA and DHA incorporation into PBMCs (P < 0.001) and lower arachidonic acid (P = 0.006) and lower production of IFN-gamma by mitogen-stimulated PBMCs (P = 0.012) and of PGE2 by lipopolysaccharide-stimulated PBMCs (P = 0.047).

Conclusion:
Dietary supplementation with fish oil plus antioxidants is associated with modified PBMC composition and lower production of PGE2 and IFN-gamma by circulating monocytes or macrophages. The response of extraintestinal manifestations of CD should be investigated in a randomized controlled trial.

Das UN. Beneficial effect(s) of n-3 fatty acids in cardiovascular diseases: but, why and how? Prostaglandins Leukot, Essent Fatty Acids 2000;63(6):351-362.

Low rates of coronary heart disease was found in Greenland Eskimos and Japanese who are exposed to a diet rich in fish oil.

Suggested mechanisms for this cardio-protective effect focused on the effects of n-3 fatty acids on eicosanoid metabolism, inflammation, beta oxidation, endothelial dysfunction, cytokine growth factors, and gene expression of adhesion molecules; But, none of these mechanisms could adequately explain the beneficial actions of n-3 fatty acids.

One attractive suggestion is a direct cardiac effect of n-3 fatty acids on arrhythmogenesis.

N-3 fatty acids can modify Na+ channels by directly binding to the channel proteins and thus, prevent ischemia-induced ventricular fibrillation and sudden cardiac death.

Though this is an attractive explanation, there could be other actions as well.
N-3 fatty acids can inhibit the synthesis and release of pro-inflammatory cytokines such as tumor necrosis factoralpha (TNFalpha) and interleukin-1 (IL-1) and IL-2 that are released during the early course of ischemic heart disease.
These cytokines decrease myocardial contractility and induce myocardial damage, enhance the production of free radicals, which can also suppress myocardial function.

Further, n-3 fatty acids can increase parasympathetic tone leading to an increase in heart rate variability and thus, protect the myocardium against ventricular arrhythmias.
Increased parasympathetic tone and acetylcholine, the principle vagal neurotransmitter, significantly attenuate the release of TNF, IL-1beta, IL-6 and IL-18.

Exercise enhances parasympathetic tone, and the production of anti-inflammatory cytokine IL-10 which may explain the beneficial action of exercise in the prevention of cardiovascular diseases and diabetes mellitus.

TNFalpha has neurotoxic actions, where as n-3 fatty acids are potent neuroprotectors and brain is rich in these fatty acids.

Based on this, it is suggested that the principle mechanism of cardioprotective and neuroprotective action(s) of n-3 fatty acids can be due to the suppression of TNFalpha and IL synthesis and release, modulation of hypothalamic-pituitary-adrenal anti-inflammatory responses, and an increase in acetylcholine release, the vagal neurotransmitter.

Thus, there appears to be a close interaction between the central nervous system, endocrine organs, cytokines, exercise, and dietary n-3 fatty acids.

This may explain why these fatty acids could be of benefit in the management of conditions such as septicemia and septic shock, Alzheimer's disease, Parkinson's disease, inflammatory bowel diseases, diabetes mellitus, essential hypertension and atherosclerosis.

PMID: 11133172