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LETTERS TO THE EDITOR
-3 fatty acids vary at different stages of inflammation
Laboratory for Vascular Biology Department of Anesthesiology and Critical Care University Hospital Tuebingen 72076 Tuebingen, Germany
To the Editor: In the August 2002 issue of the American Journal of Physiology-Heart Circulatory Physiology, Mayer and colleagues (8) examined the ability of 
-3 fatty acids to suppress monocyte adhesion to human endothelial cells. Combining immunofluorescence with a flow chamber assay, their experiment surmounted the limitations of previous studies that have investigated the effects of -3 fatty acids mainly using static adhesion assays (4, 12). However, their finding that -3 fatty acids do not attenuate the expression of E-selectin, ICAM-1, and VCAM-1 is remarkably different from previous publications (2–4), which reported a marked downregulation of these molecules. Mayer et al. (8) suggest that these discrepancies may have been due to different concentrations of the fatty acids used in the assays. Although downregulation of endothelial cell adhesion molecules by -3 fatty acids is indeed dose dependent (3), the effect of incubation times may be even more important for the interpretation of their results. It has been shown that the inhibition of VCAM-1 by docosahexaenoic acid (DHA) is dependent on the preincubation time (3). Therefore, the 6-h preincubation in their assay might have been too short to detect an effect on adhesion molecule expression (8). Additionally, prolonged cytokine treatment results in a model of sustained inflammation in which temporary upregulation of E- and P-selectin declines down to baseline (1, 11). E-selectin showed only a weak upregulation in their experiment, and P-selectin was completely absent from the cell surface after 20 h of incubation with tumor necrosis factor (TNF-
). This indicates that monocyte adhesion was hardly mediated by selectins but became more dependent on interactions among leukocytic integrins, ICAM-1, VCAM-1, and platelet-activating factor (8). We observed different effects of -3 fatty acids on monocyte-endothelial interactions using short-term cytokine treatment (6 h TNF-) in the same experimental design as that of Mayer et al. After pretreatment with a fish oil emulsion for 24 h, expression of E-selectin, ICAM-1, and VCAM-1 on cytokine-activated endothelium was suppressed, whereas upregulation of P-selectin was not attenuated. The typical increase in rolling velocity showed that P-selectin compensated for the decrease in E-selectin, and the number of rolling monocytes could not be reduced by the fish oil emulsion. Although firm adhesion decreased significantly, the sustained rolling interactions were sufficient to induce tissue factor expression on interacting monocytes (9). These contrasting effects of fish oil on monocyte adhesion might be relevant for diseases in which P-selectin is especially important, as in atherosclerosis and ischemia-reperfusion (7, 13). As far as we know, there are only three studies that have addressed the effects of -3 fatty acids on leukocyte rolling. In addition to the study of Mayer et al. and our own investigation, Lehr et al. (6) examined the effects of dietary fish oil on leukocyte accumulation in an animal model of 4 h ischemia-reperfusion. As might be expected from our results on early inflammation, they observed a marked reduction in adherent leukocytes, whereas rolling interactions remained unaffected (6). Regarding both the absence of P-selectin in the model of Mayer et al. and the apparent differences in monocyte adhesion, it seems that the effects of -3 fatty acids on endothelial activation, leukocyte accumulation, and coagulation vary during different stages of inflammation. Apart from P-selectin expression, differences between time and concentration in both experimental designs might have influenced enzymatic transformation of DHA. These di- and trihydroxygenated products, namely docosatrienes and resolvins, downregulate leukocyte infiltration and are thought to represent stop signals during resolution of inflammation (5, 10). Because neither Mayer et al. nor we attempted to measure these autacoids, it remains unknown whether the different incubation settings affected their formation and thus accounted for the experimental differences between both studies. Careful evaluation of such time-dependent effects may be needed to establish dietary treatment protocols that take into consideration the temporal course of underlying disease.
REFERENCES
-3 Fatty acids suppress monocyte adhesion to human endothelial cells: role of endothelial PAF generation. Am J Physiol Heart Circ Physiol 283: H811–H818, 2002; 10.1152/ajpheart.00235.2002.Medizinische Klinik II Department of Internal Medicine Justus Liebig University 35392 Giessen, Germany
To the Editor: The impact of -3 fatty acids on the expression of adhesion molecules and functional consequences in endothelial cells is not completely understood. The use of high concentrations of free fatty acids or lipid emulsions results in an inhibition of stimulated expression of E-selectin, ICAM-1, and VCAM-1 (1, 6, 9).
We agree with Nohé et al. that in addition to physiological concentrations of the fatty acids employed in our setting, other experimental conditions such as the duration of preincubation time with -3 fatty acids and stimulation time with tumor necrosis factor- (TNF-) may be responsible for the lack of impact on upregulation of adhesion molecules (4). Corroborating our results, Sethi et al. (7) found an unchanged upregulation of adhesion molecules by eicosapentaenoic acid (a major -3 fatty acid) in endothelial cells. Instead, they presented oxidized eicosapentaenoic acid as an effective inhibitor of TNF--induced upregulation of adhesion molecules (7). In addition, a recent investigation focused on new antiinflammatory products derived from -3 fatty acids via enzymatic pathways: resolvins and docosatrienes. Highly effective in submicromolar concentration both in vivo and in vitro; they inhibit leukocyte transmigration and generation of inflammatory cytokines (3).
Furthermore, the impact of -3 fatty acids on rolling and adhesion may be modulated by presence or absence of P- and E-selectin as well as the upregulation of ICAM-1 and VCAM-1 on endothelial cells. However, -3 fatty acids are able to modulate immune responses of leukocytes and endothelial cells via different mechanisms. First, by interfering with the activation of nuclear factor-
B, docosahexaenoic acid inhibits (at high concentrations) the upregulation of adhesion molecules (9). Second, TNF- increases susceptibility to free fatty acids, and -3 fatty acids are rapidly incorporated into the membrane lipids of endothelial cells under these conditions (5). Phospholipid pools are thereby massively altered toward an increase in the -3-to--6 fatty acid ratio with subsequent changes in intra- and intercellular signal transduction (lipid signaling). Because generation of platelet-activating factor (4) and probably formation of inositol phosphates (as described for neutrophils (8)) are reduced, changes in lipid signaling may lead to less adhesive power. Third, generation and impact of inflammatory lipid mediators derived from arachidonic acid such as prostaglandins or leukotrienes are reduced by -3 fatty acids due to competitive metabolism and antiinflammatory properties of -3 products formed (2, 3). Because of all these alterations, -3 fatty acids may differentially impact rolling and adhesion of leukocytes compared with -6 fatty acids (e.g., arachidonic acid). The strength and character of impact induced by -3 fatty acids may vary according to experimental conditions. Despite differences in the experimental setting, Nohé et al. (6), we (4), and others (7, 9) were able to demonstrate a reduction of adhesion of monocytes to endothelial cells by -3 fatty acids, which will probably be operative in acute and chronic inflammatory diseases.
REFERENCES
-3 Fatty acids suppress monocyte adhesion to human endothelial cells: role of endothelial PAF generation. Am J Physiol Heart Circ Physiol 283: H811–H818, 2002. impact of -3 vs. -6 fatty acids. J Lipid Res 43: 944–951, 2002.-3 fatty acids in fish oil inhibit leukocyte-endothelial interactions through activation of PPAR. Blood 100: 1340–1346, 2002.-3 polyunsaturated fatty acids inhibit phosphoinositide formation and chemotaxis in neutrophils. J Clin Invest 91: 651–660, 1993.[ISI][Medline]
. Arterioscler Thromb Vasc Biol 15: 622–628, 1995.This article has been cited by other articles:
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  X. Wang, W. Li, N. Li, and J. Li {omega}-3 Fatty Acids-Supplemented Parenteral Nutrition Decreases Hyperinflammatory Response and Attenuates Systemic Disease Sequelae in Severe Acute Pancreatitis: A Randomized and Controlled Study JPEN J Parenter Enteral Nutr, May 1, 2008; 32(3): 236 - 241. [Abstract] [Full Text] [PDF]
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