INFLAMMATION AND LONG-CHAIN N-3 POLYUNSATURATED FATTY ACIDS

OBJECTIF NUTRITION 82 (JANUARY 2007)
by Prof. Jacques Delarue, Laboratoire Régional de Nutrition Humaine (CHU Cavale Blanche, Brest)

Inflammation is a subject of major concern for nutritionists. Indeed, local inflammation is likely to result in systemic inflammation leading to severe undernourishment. Chronic inflammation, which characterizes certain diseases, is accompanied by chronic undernourishment. For all these reasons, anything that can reduce inflammation is also likely to have beneficial effects on nutritional status. Moreover, certain nutrients can modulate inflammation. This is the case with long-chain n-3 polyunsaturated fatty acids (LC n-3-PUFA).

THE INFLAMMATORY REACTION

Cellular events
The inflammatory reaction is the superior organism¡¯s means of defense against foreign aggressions (infection, injury). Its purpose is to eliminate the pathogenic agent and repair the damaged tissue. The four cardinal signs of this reaction are redness, edema, heat and pain. They result in increased blood flow, greater capillary permeability allowing the complement, antibodies and cytokines to pass through the endothelial barrier, and the migration of leucocytes towards the damaged tissue.
The first phase of the inflammatory reaction is the recognition of the pathogenic agent, which initiates the reaction. The second phase takes place in the proximity of the blood vessels and involves the proteolytic plasmatic systems (the complement, bradykinin, thrombine): they increase vascular permeability, produce a chimiotactic effect and activate endothelial cells, neutrophilic leukocytes and monocytes. The third phase is characterized by the arrest and then the extravasation of mononuclear cells around the area where the pathogenic agent is located. The activated cells release inflammation mediators, some of which are lipidic novo molecules synthesized from cellular membrane phospholipids. From membrane phospholipids, phospholipase A2 releases arachidonic acid, from which 5-lipoxygenase and cyclo-oxygenase 2 will respectively generate 4-series leucotrienes and 2-series prostaglandines, which are all pro-inflammatory (Box 2).
Furthermore, the activation of NADPH-oxydase produces bactericidal and highly cytotoxic free radicals, while the activation of macrophage NO-synthase produces nitrogen oxide (NO), which are responsible, together with free radicals, for generating peroxynitrites.
Pro-inflammatory cytokines (TNF-¥á, IL-1©¬, IL6) participate in both local and systemic inflammatory reactions, at a distance from the areas concerned by the pathogenic agent. An inappropriate or uncontrolled inflammatory reaction will lead, via these cytokines, to tissue destruction (endotoxemic shock, adult respiratory distress syndrome) or, in certain cases, a chronic inflammatory disease (rheumatoid arthritis, chronic inflammatory disease of the intestines, and so on). Depending on the degree of cytokine production, more or less severe changes in the nutritional status can thus be observed, concerning both fat and lean body mass.

Molecular events
The principal promoter of pro-inflammatory response is the nuclear factor kappa B (NF-kB). NF-kB is a transcription factor found in the cytoplasm in the inactive form of a dimer associated with an inhibiting sub-unit, IkB. The IkB release from the active dimer is the essential cytosolic signalization mechanism of inflammation. Given its pivotal role, NF-kB is a target for modulation of the inflammatory response. It should be stressed that the cell also has an anti-inflammatory defense system: thermal shock proteins. The involvement of thermal shock proteins is non-specific. It protects against subsequent oxidative stress and helps minimize cellular response to pro-inflammatory stimuli.

INFLAMMATION AND ARACHIDONIC ACID

Phospholipase A2 releases PUFA, which are esterified in the membrane phospholipids.
Arachidonic acid is the most represented in the membranes, meaning that it is the main substrate of eicosanoid synthesis: series-4 leucotrienes and 5-HETE, prostaglandins and series-2 thromboxanes (Box 2). Eicosanoids are involved in modulating the intensity and duration of the inflammatory response. Arachidonic acid content in the cells is highly correlated with their capacity to produce eicosanoids such as PGE². An increase in arachidonic acid content in food boosts the arachidonic acid concentration in the inflammatory cells. Nutritional supplementation with 1.5 g/d of arachidonic acid for seven weeks induces a noticeable increase in PGE2 and LTB4 production by mononuclear cells, stimulated by endotoxin. This does not, however, alter the production of pro-inflammatory cytokines.

INFLAMMATION AND LC N-3 PUFA

The multiple anti-inflammatory effects of LC N-3 PUFA (Box 3) have been demonstrated in the tissue of patients suffering from chronic inflammatory diseases, especially rheumatoid arthritis.

These effects come into play through several mechanisms: a pronounced reduction in the inflammatory reaction by a decline in the synthesis of leucotrienes B4, protaglandine E2, thromboxane B2, 5-HETE and inhibited production of pro-inflammatory cytokines: TNF-¥á IL-1©¬ and IL-6. The incorporation of LC-n-3 PUFA in mononuclear cell membranes very likely plays a role in the inhibiting effect of LC n-3 PUFA on the production of pro-inflammatory cytokines. The eicosanoids derived from the LC n-3-PUFA are approximately 100 times less active in the inflammatory process than those derived from arachidonic acid. Finally, cyclo-oxygenase 2 generates series-E resolvins from the EPA and series-D resolvins from docosatrienes and neuroprotectines. All these molecules have an anti-inflammatory effect.
The PUFA content of cellular membrane phospholipids stands directly in relation to the nutritional intake of LC n-3 and n-6 PUFA (Box 4). The LC n-3 PUFA modulate the inflammatory reaction especially by a competition mechanism at the level of cyclooxygenase and lipoxygenase, resulting in a reduced release of pro-inflammatory arachidonic acid metabolites.

LC N-3-PUFA AND CHRONIC INFLAMMATORY DISEASES

• A chronic autoimmune inflammatory disease, rheumatoid arthritis is characterized as chronic symmetric and deforming polyarthritis. Articular lesions show synovial membrane infiltration by activated T lymphocytes, macrophages and cellules and activated ß lymphocytes, on the one hand, and by a proliferation of synoviocytes, on the other hand. The susceptibility and evolutivity of rheumatoid arthritis result from a genetic predisposition concerning the genes of the major histocompatibility complex. The release of pro-inflammatory cytokines into the synovial membrane activates destructive proteolytic enzymes, sub-chondral osteoclastes and neutrophilic leukocytes.
The cellular and molecular effects of LC n-3-PUFA have been demonstrated in the concerned tissue by chronic inflammation in the course of rheumatoid arthritis. Various studies on the effect of n-3 on the evolution of these two diseases were resumed in Calder´s review and in a very recent meta-analysis. Given the physiopathology of rheumatic arthritis and the effects of LC n-3-PUFA on inflammation, it was to be expected that these fatty acids could modulate inflammation in the course of the disease. In-vitro studies have shown that the incorporation of activated chondrocytes into membranes inhibited certain proteolytic enzymes as well as the expression of IL1, TNF-α and COX2. A recent meta-analysis of clinical studies concluded that n-3 had no effect on pain, articular involvement, sedimentation rate or the evolutivity index. By contrast, n-3 reduced the necessary doses of non-steroidal anti-inflammatory drugs and corticoids.
• A recent review and meta-analysis concluded that arguments were insufficient in favor of an LC n-3-PUFA effect on remission, evolutivity, relapse frequency and corticoid doses in the course of ulcerative colitis and Crohn´s disease.

Conclusion

Long-chain n-3 polyunsaturated fatty acids (LC n-3-PUFA) have an anti-inflammatory effect thanks to two mechanisms, including a first indirect effect, i.e. decreased production of pro-inflammatory eicosanoids, and a second direct effect, i.e. decreased expression of the genes involved in the inflammatory cascade. In vivo, this anti-inflammatory effect is well documented with respect to rheumatoid arthritis. It remains uncertain in the course of chronic inflammatory diseases of the intestines.

References