(21-09-06) Inflammatory Markers in Healthy Italian Adults: Are n-6 PUFAs Pro-Inflammatory?

Consumption of omega-3 polyunsaturated fatty acids (n-3 PUFAs) is associated with anti-inflammatory responses in blood vessels, immune cells, cardiovascular disease, inflammatory diseases such as asthma and rheumatoid arthritis, and neurodegenerative diseases like Alzheimer??s disease. In contrast, omega-6 PUFAs, such as linoleic and arachidonic acids, have mainly proinflammatory effects in these conditions. However, relationships between individual fatty acids and specific immune modulators are not clear-cut.

In healthy people, dietary n-3 PUFAs, especially the long-chain (LC) forms, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), generally reduce the production of inflammatory mediators. Decreases in the cytokines TNF-alpha, and IL-6 and vascular adhesion molecules may depend on??, IL-1??TGF- dose, sex and other factors. Lower inflammatory markers have also been associated with increased fish consumption. Relationships between individual inflammatory markers in serum and specific PUFAs in plasma have not been well characterized in the general population. Whether circulating levels of individual PUFAs are linked to concentrations of pro- and anti-inflammatory cytokines was investigated in detail in a representative population sample of men and women ranging from 20 to over 85 years of age. The total sample of 1,123 participants from Tuscany, Italy, excluded people with dementia and included 69% aged 65 to 84 years.


General findings on total plasma fatty acid concentrations included higher concentrations among older participants compared with younger ones, similar levels in men and women, and positive associations with total cholesterol and triglycerides, but a negative association with high-density lipoproteins. As a percent of total fatty acids, n-3 and n-6 PUFAs accounted for 3.4% and 33.1%, respectively. Percentages were significantly lower in older compared with younger ones.

Lower concentrations of arachidonic acid (AA) and DHA were significantly associated with higher concentrations of the pro-inflammatory cytokines interleukin-6 and -1ra and lower transforming (Figures 1 and 2). Lower DHA was also associated with lower??growth factor- concentrations of the anti-inflammatory cytokine, interleukin-10. Alpha-linolenic acid was significantly and inversely associated with interleukin-1ra. Linoleic acid concentration was not significantly associated with any cytokine examined.*


When the investigators examined the concentrations of 8 cytokines by quartiles of total n-3 and n-6 PUFA concentrations, the lowest quartile of n-3 PUFAs was associated with significantly higher concentrations of Interleukin-6, -1ra, TNF-alpha, and C-reactive protein, pro-inflammatory cytokines or mediators of acute phase immune defenses. Lower concentrations of n-3 PUFAs were also associated with lower concentrations of the anti-inflammatory cytokines interleukin-10 and -6r and transforming growth factor-beta. These observations are consistent with the overall anti-inflammatory effects of n-3 PUFAs.

Interestingly, a similar pattern of associations was observed for total n-6 PUFAs, with the exception of the anti-inflammatory cytokine, interleukin-10. For 6 of the 8 cytokines, the differences between the highest and lowest quartiles of intake were statistically significant. However, in multivariate analysis, the trend for a dose-response relationship with n-6 PUFAs was statistically significant for only 2 cytokines, interleukin-1ra and transforming growth factor-beta. A similar pattern of cytokine responses to dietary n-3 and n-6 PUFAs is inconsistent with the view that n-6 PUFAs have predominantly pro-inflammatory effects.

The strength of the statistical relationships observed for n-3 PUFAs and for lower n-6 PUFAs with higher interleukin-1ra and lower transforming growth factor-beta were confirmed in additional analyses conducted separately in men and women, participants 65 years and older, and those free of cardiovascular diseases.

Relationships with some of these inflammatory markers, particularly interleukin-1ra and interleukin-6r, are especially complex. Interleukin-1ra is an acute-phase protein seen in inflammation, but it antagonizes the pro-inflammatory cytokine interleukin-1 and prevents tissue damage. Its reduction with higher levels of n-3 and n-6 PUFAs suggests an anti-inflammatory effect of these fatty acids. Interleukin-6r and interleukin-6 appear to have opposite biological activities, being anti-inflammatory and pro-inflammatory, respectively. However, the function of interleukin-6r is not well understood.

The most striking observation is that both n-6 and n-3 PUFAs, particularly AA and DHA, were associated with inflammatory markers in similar ways. This observation has been reported previously, but in less detail than here.

The authors noted that this population consumes an average of 7.4 g total PUFAs/day, about half the consumption in the U.S. Nearly half the dietary fat intake is monounsaturated. It is conceivable that with a high background diet of monounsaturates and the ratio of n-6 to n-3 fatty acids less extreme than in other western countries the effects of both classes of PUFAs on inflammatory markers is modified. What the study makes clear is that simple generalizations about the pro- and anti-inflammatory effects of dietary n-6 and n-3 PUFAs are just that?Xtoo simple.


Ferrucci L, Cherubini A, Bandinelli S, Bartali B, Corsi A, Lauretani F, Martin A, Andres-Lacueva C, Senin U, Guralnik JM. Relationship of plasma polyunsaturated fatty acids to circulating inflammatory markers. J Clin Endocrinol Metab 2006; 91:439-446. [PubMed]
Source: PUFA Newsletter

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