Investigations into the mechanisms by which fats modulate the inflammatory response to cytokines

Clamp, Alan Grenville (1994) Investigations into the mechanisms by which fats modulate the inflammatory response to cytokines. University of Southampton, Doctoral Thesis.

Abstract

The hypothesis was proposed that diet-induced changes in the fatty acid composition of target-tissue plasma membrane influence cytokine signal transduction, thereby modulating the inflammatory response. A number of experiments were undertaken to assess whether diet can influence the physicochemical properties of the rat hepatocyte plasma membrane, and thereby alter the inflammatory response to TNFα or IL-6. The possibility that diet-induced changes in target tissue responsiveness may be mediated by modulation of the hepatocyte TNFα receptor was investigated.

Feeding diets of differing fatty acid composition and content radically altered the chemical composition, but not the physical properties, of rat hepatocyte plasma membranes. Observed alterations in the spectrum of eicosanoid precursor fatty acids, phospholipid class distribution and membrane cholesterol content, have the potential to influence metabolic responses to TNFα. The inflammatory response to IL-6 was found to be largely independent of any modulation by fats, suggesting that dietary lipid modulation of metabolic responses to TNFα in vivo is due to changes in cytokine production and/or an alteration in the hepatic response to TNFα. Increased availability of the n-3 fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), whether in cell culture medium or through the diet, was associated with an increase in TNFα-stimulated IL-6 production. This would be expected to result in a suppression of the inflammatory response. Attenuation of the hepatic response to TNFα in vitro, and up-regulation of hepatocyte TNFα receptor affinity, was observed following incubation of hepatocytes with DHA, probably via the inhibition of intracellular protein kinase C (PKC).

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