MODULATION OF PRO-INFLAMMATORY CYTOKINE BIOLOGY BY UNSATURATED FATTY-ACIDS

The production of pro-inflammatory cytokines, such as interleukins 1 a nd 6 and tumour necrosis factors, occurs rapidly following trauma or i nvasion of the body by pathogenic organisms. The cytokines mediate the wide range of symptoms associated with trauma and infection, such as fever, anorexia, tissue wasting, acute phase protein production and im munomodulation. In part, the symptoms result from a co-ordinated respo nse, in which the immune system is activated and nutrients released, f rom endogenous sources, to provide substrate for the immune system. Al though the cytokine mediated response is an essential part of the resp onse to trauma and infection, excessive production of pro-inflammatory cytokines, or production of cytokines in the wrong biological context , are associated with mortality and pathology in a wide range of disea ses, such as malaria, sepsis, rheumatoid arthritis, inflammatory bowel disease, cancer and AIDS [1]. Cytokine biology can be modulated by an tiinflammatory drugs, recombinant cytokine receptor antagonists and nu trients. Among the nutrients, fats have a large potential for modulati ng cytokine biology. A number of trials have demonstrated the antiinfl ammatory effects of fish oils, which are rich in n-3 polyunsaturated f atty acids, in rheumatoid arthritis, inflammatory bowel disease, psori asis and asthma. Animal studies, conducted by ourselves and others, in dicate that a range of fats can modulate pro-inflammatory cytokine pro duction and actions. In summary fats rich in n-6 polyunsaturated fatty acids enhance IL1 production and tissue responsiveness to cytokines, fats rich in n-3 polyunsaturated fatty acids have the opposite effect, monounsaturated fatty acids decrease tissue responsiveness to cytokin es and IL6 production is enhanced by total unsaturated fatty acid inta ke [2-4]. There are a large number of potential cellular mechanisms wh ich may mediate the effects observed. The majority relate to the abili ty of fats to alter the composition of membrane phospholipids. As a co nsequence of alterations in phospholipid composition, membrane fluidit y may change, altering binding of cytokines to receptors and G protein activity. The nature of substrate for various signalling pathways ass ociated with cytokine production and actions may also be changed. Cons equently, alterations in eicosanoid production and activation of prote in kinase C may occur. We have examined a number of these potential me chanisms in peritoneal macrophages of rats fed fats with a wide range of fatty acid composition. We have found that the total C18:2 and 20:4 diacyl species of phosphatidylethanolamine in peritoneal macrophages relates in a positive curvilinear fashion with dietary linoleic acid i ntake; that TNF induced IL1 and IL6 production relate in a positive cu rvilinear fashion to linoleic acid intake; that leukotriene Bq product ion relates positively with dietary linoleic acid intake over a range of moderate intakes and is suppressed at high intakes, while PGE(2) pr oduction is enhanced. There was no clear relationship between linoleic acid intake and membrane fluidity, however fluidity was influenced in a complex manner by the type of fat in the diet, the period over whic h the fat was fed and the presence of absence of TNF stimulation. None of the proposed mechanisms, acting alone, can explain the positive ef fect of dietary linoleic acid intake on pro-inflammatory cytokine prod uction. However each may be involved, in part, in the modulatory effec ts observed.