As a regulator of cellular inflammation and proliferation, cytosolic phospholipase A₂ α (cPLA₂α) is a promising therapeutic target for psoriasis; indeed, the cPLA₂α inhibitor AVX001 has shown efficacy against plaque psoriasis in a phase I/IIa clinical trial. To improve our understanding of the anti-psoriatic properties of AVX001, we sought to determine how the compound modulates inflammation and keratinocyte hyperproliferation, key characteristics of the psoriatic epidermis. We measured eicosanoid release from human peripheral blood mononuclear cells (PBMC) and immortalized keratinocytes (HaCaT) and studied proliferation in HaCaT grown as monolayers and stratified cultures. We demonstrated that inhibition of cPLA₂α using AVX001 produced a balanced reduction of prostaglandins and leukotrienes; significantly limited prostaglandin E₂ (PGE₂) release from both PBMC and HaCaT in response to pro-inflammatory stimuli; attenuated growth factor-induced arachidonic acid and PGE₂ release from HaCaT; and inhibited keratinocyte proliferation in the absence and presence of exogenous growth factors, as well as in stratified cultures. These data suggest that the anti-psoriatic properties of AVX001 could result from a combination of anti-inflammatory and anti-proliferative effects, probably due to reduced local eicosanoid availability.

中文翻译：

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cPLA2α酶抑制可减轻炎症和角质形成细胞增殖。

随着蜂窝炎症和增殖的调控，细胞溶质磷脂酶A ₂ α（与cPLA ₂ α）是有前景的治疗牛皮癣目标; 事实上，与cPLA ₂ α抑制剂AVX001已经显示出在相I / IIA临床试验对斑块型银屑病的功效。为了更好地了解AVX001的抗银屑病特性，我们试图确定该化合物如何调节炎症和角质形成细胞过度增殖（银屑病表皮的关键特征）。我们测量了人类外周血单核细胞（PBMC）和永生化角质形成细胞（HaCaT）中类花生酸的释放，并研究了以单层和分层培养形式生长的HaCaT中的增殖。我们证明了抑制cPLA ₂使用AVX001产生的α平衡减少了前列腺素和白三烯；响应促炎性刺激，PBMC和HaCaT释放的前列腺素E ₂（PGE ₂）明显受限；HaCaT的生长因子诱导的花生四烯酸和PGE ₂释放减弱；在不存在和存在外源性生长因子以及分层培养物中，抑制角质形成细胞的增殖。这些数据表明，AVX001的抗银屑病性质可能是抗炎和抗增殖作用的组合，可能是由于局部类花生酸的可利用性降低所致。