The mechanism of action of secreted phospholipase A2 and its inhibition in inflammation

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Secretory phospholipase A2 (sPLA2) is an important mediator of inflammation and is clinically associated with the onset and severity of several immune-mediated diseases including arthritis, asthma, atherosclerosis, psoriasis and recently prostate cancer. These are complex diseases which are poorly understood. We have shown that sPLA2 can by itself and in combination with inflammatory cytokines modulate signalling pathways in cells derived from the joints of patients with arthritis to upregulate inflammatory molecules. How this happens is completely unknown. We plan to work out how this enzyme does this. We have also developed small cyclic peptide inhibitors of sPLA2 which potently block the function of the enzyme in these cells. We plan to determine how this happens and if these inhibitors are effective at blocking inflammation and arthritis. The proposal may identify new mechanisms by which secreted factors upregulate inflammation in human cells and may lead to the discovery of new ways to intervene to block these pathways.