NEUTROPHIL OXYGEN RADICAL GENERATION - SYNERGISTIC RESPONSES TO TUMOR-NECROSIS-FACTOR AND MONO POLYUNSATURATED FATTY-ACIDS

In inflammatory reactions there are complex interactions of protein me diators (cytokines) and mediators derived from lipids. An important ev ent in inflammation is superoxide production, in relation to microbici dal activity as well as tissue damage, We have studied interactions of lipid mediators with a cytokine mediator tumor necrosis factor alpha (TNF) in stimulating superoxide production by human neutrophils for th is reason and because it throws light on intracellular signals activat ing this response. Pretreatment of neutrophils with TNF markedly augme nted the amount of superoxide produced in response to AA but not to ei ther a 20 carbon saturated fatty acid, or the hydroxy- or hydroperoxy- derivatives of AA. Not only were other polyunsaturated fatty acids (ei cosapentanoic, docosahexaenoic, linolenic, linoleic acid) as effective as AA but so was the monounsaturated fatty acid, oleic acid. Indeed T NF primed the neutrophils for an increased response to a major mediato r of inflammation, leukotriene B-4, which is a product of AA metabolis m via the lipoxygenase pathway, The data demonstrate that two major ty pes of mediators generated during an inflammatory response have synerg istic action on neutrophils in the generation of reactive oxygen speci es. In contrast, neutrophils primed with TNF and challenged with PGE(2 ), a product of AA metabolism via the cyclooxygenase pathway, showed a reduced chemiluminescence response. This identifies an important inte raction between unsaturated lipids and cytokines which is likely to pl ay a critical role in disease processes and nutrient modulation of the immune responses.