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

分泌型磷脂酶A2(SPLA2)是一种重要的炎症介质，临床上与多种免疫介导性疾病的发生和严重程度有关，包括关节炎、哮喘、动脉粥样硬化、银屑病以及最近的前列腺癌。这些都是复杂的疾病，人们对此知之甚少。我们已经证明，sPLA2本身可以与炎症细胞因子结合，调节关节炎患者关节细胞中的信号通路，上调炎症分子。这是如何发生的，完全是未知的。我们计划弄清楚这种酶是如何做到这一点的。我们还开发了sPLA2的小环肽抑制剂，它可以有效地阻断这些细胞中的酶功能。我们计划确定这是如何发生的，以及这些抑制剂是否有效地阻止炎症和关节炎。这项提议可能会确定分泌因子上调人类细胞炎症的新机制，并可能导致发现新的干预方法来阻断这些途径。

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.