Title: Inflammation and Cytokines

Key words: Omega 3 fatty acids, cytokines, leucotrienes, PUFA, prostaglandins

Date: Jan 2000

Category: 1. The Cell

Type: Article

Author: Dr van Rhijn

 

Inflammation and Cytokines

How Omega-3 Fatty Acids Modulate Pro-Inflammatory Cytokine Production.

Introduction

Inflammatory and immune processes are mediated by a diverse range of molecules. Among these are pro-inflammatory cytokines (interleukins - IL), triggered by tumour necrosis factor (TNF)1. The cytokines cause the generation of fever as a protective action, and also result in production of acute-phase protein, reactive oxygen species etc2. However, if produced inappropriately, they may also be associated with damaging pathology in a wide range of disorders3. A number of agents can down-regulate cytokine effects, including nutrients. Cytokine modulation by nutrients such as n-3 fatty acids is the topic of this article.

Mechanism

The most likely site where lipids might modulate inflammation is in the cell membrane. Incorporation of dietary polyunsaturated fatty acids (PUFA) into the various classes of phospholipids (sn-2 position) can alter the composition of the fatty acyl chains of membrane phospholipids, thereby exerting a biophysical influence by altering the fluidity characteristics of the membrane. Although the effect on membrane fluidity appears to be an acute but temporary effect4, it may influence the activity of membrane-associated enzymes (e.g. G proteins). These are important in controlling cytokine production and the affinity with which cytokines bind to their specific membrane receptors5.

G-protein affects adenylate cyclase and phospholipase A2 (PL A2) activity, giving rise to prostaglandins (PG) and leucotrienes (LT). The altered membrane function may also affect protein kinase C activity6 (activation requires hydrolysis of phosphatidylinositol and presence of phosphatidylserine) and together be able to mediate the inflammatory response by modulating TNF, IL-17 & IL-68. Eicosapentaenoic acid (EPA, C20:5 w -3) is incorporated with the highest affinity of all PUFA's9, and is converted into precursors of eicosanoids (which regulate cytokine production10) of the less potent PG3 and LT5 series11. n-3 PUFA decrease PGE2 production, which inhibits production of TNF12, IL-1 and IL-613.

Studies

Numerous studies have confirmed that fats rich in n-3 PUFA (fish oils) exert a generalised anti-inflammatory influence, for example by reducing TNF a 14, IL-1b 15, IL-1a 16, IL-217 and IL-618 production by mononuclear cells. Animals fed on fish oil experienced a smaller fever in response to IL-1 (guinea-pigs)19, murine macrophages showed decreased TNF20 and IL-6 production21 and exhibited a lesser degree of anorexia in response to IL-1 (rats)22 or TNF23 compared to other oils.

Dietary fish (rich in EPA) and coconut oil (low in linoleic acid) fed to rats, resulted in high lateral fluidity (in peritoneal macrophages & hepatocytes) and suppressed pro-inflammatory cytokine production (TNF & IL-124) and responsiveness of tissue to inflammatory agents. Other fats (butter, olive & maize) had opposing effects25. In patients undergoing major surgery26, n-3 PUFA (EPA) reduced cytokine levels and altered the leukotriene ratio LTB4/LTB5 towards an anti-inflammatory one, by increasing the LTB5 levels.

Conclusion

The mechanisms whereby dietary fats modulate inflammation and alter the composition of plasma membranes in cells producing pro-inflammatory cytokines are still not fully understood. However, it is clear that n-6 PUFA and cholesterol exert a pro-inflammatory influence whilst n-3 PUFA exert the opposite effect (by reducing immuno modulatory factors). This suggests that supplementation with n-3 PUFA may be of benefit in chronic inflammatory conditions27.

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