The overall objective of this proposal is to investigate how dietary omega-3 polyunsaturated fatty acids (PUFA) affect signal transduction and cell functions in chemotaxin-stimulated neutrophils in order to further our understanding of the relevant signal transduction pathways and to gain insight into the cellular defect in neutrophils of patients with rheumatoid arthritis (RA) and the mechanism of its reversal by dietary manipulation. Per capita consumption of fish, which contain omega-3 PUFA, has been rising in the US, probably due to favorable attention in the lay press regarding the beneficial effects in the prevention and treatment of ischemic heart disease and regarding its antiinflammatory effects which have been demonstrated with some efficacy in the treatment of RA, despite the use of low dosages of omega-3 PUFA in the clinical trials. My recent data demonstrate that dietary omega-3 PUFA inhibit phosphoinositide formation in the neutrophils of healthy subjects stimulated with leukotriene B4 (LTB4) or platelet-activating factor (PAF). The data suggest that the inhibition of neutrophil chemotaxis in healthy subjects is due to post-receptor inhibition of the LTB4 and PAF signals via the phosphatidylinositol (PI) selective phospholipase C (PLC) as evidenced by dramatically decreased formation of inositol triphosphate (IP3) in the absence of a significant effect on the number of affinity of the respective receptors. As there is a significant correlation between functional attenuation, inhibition of IP3 generation and incorporation of the omega-3 PUFA, EPA, into the PI pool, I propose to localize the site of action of the omega-3 PUFA in the signal transduction pathway of neutrophils. In patients with RA, neutrophil chemotaxis is decreased compared with healthy subjects and paradoxically increases towards normal levels after dietary omega-3 PUFA. I propose to localize the site of the defect in the baseline chemotaxis of neutrophils from patients with RA and to assess how dietary omega-3 PUFA paradoxically increase signal transduction in the neutrophils of patients with RA. The investigations of potential causes of the impaired baseline chemotaxis in neutrophils of RA patients and the aberrant effects of dietary omega-3 PUFA on the signal transduction pathway of the chemotaxin-stimulated neutrophils of patients with RA are also directed to further the understanding of the pathobiological changes in the relevant signal transduction pathways.
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