Suppression of cytokine synthesis, integrin expression and chronic inflammation by inhibitors of cytosolic phospholipase A(2)
Suppression of cytokine synthesis, integrin expression and chronic inflammation by inhibitors of cytosolic phospholipase A(2)
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DOI：
10.1016/s0014-2999(97)85419-2
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发表时间：
1997-05-20
影响因子：
5
通讯作者：
Scheuer, WV
中科院分区：
文献类型：
--
作者：
AmandiBurgermeister, E;Tibes, U;Scheuer, WV
为了确定在炎症中活跃的磷脂酶A(2)的异构体，我们评估了分泌型和胞质型磷脂酶A(2)的低分子量抑制剂的作用。我们发现胞质磷脂酶A(2)抑制剂在慢性炎症（大鼠佐剂性关节炎）的体内模型中具有治疗效果，而分泌型磷脂酶A(2)抑制剂则没有有益作用。在体外，胞质磷脂酶A(2)抑制剂通过降低mRNA水平，降低钙离子载体上Mac-1 (CD11b/CD18) β(2)-整合素的表面表达，刺激人血液粒细胞，并抑制脂多糖刺激的人血液单核细胞和U937细胞中白细胞介素-1 β的合成。脂质介质促进Mac-1的胞吐和白细胞介素-1 β的转录，从而进一步提高胞质磷脂酶A(2)的活性和表达。因此，胞质磷脂酶A(2)的超诱导可能建立一个正反馈回路，将急性炎症转化为慢性炎症。因此，胞质磷脂酶A(2)抑制剂可能通过干扰细胞活化和浸润来预防体内炎症。我们得出结论，胞质磷脂酶A(2)而非分泌磷脂酶A(2)是炎症信号传导的主要酶。
To define the isoform of phospholipases A(2) active in inflammation we evaluated the effects of low-molecular-weight inhibitors of secretory and cytosolic phospholipases A(2). We found that inhibitors of cytosolic phospholipase A(2) had therapeutic efficacy in an in vivo model of chronic inflammation (rat adjuvant arthritis), whereas inhibitors of secretory phospholipase A(2) had no beneficial effect. In vitro, inhibitors of cytosolic phospholipase A(2) diminished surface expression of Mac-1 (CD11b/CD18) beta(2)-integrin on calcium ionophore stimulated human blood granulocytes and suppressed synthesis of interleukin-1 beta in lipopolysaccharide-stimulated human blood monocytes and U937 cells by reducing mRNA levels. Lipid mediators promote Mac-1 exocytosis and transcription of interleukin-1 beta, which further enhances cytosolic phospholipase A(2) activity and expression. Thus, superinduction of cytosolic phospholipase A(2) may establish a positive feedback loop, converting acute inflammation into chronic inflammation. Consequently, inhibitors of cytosolic phospholipase A(2) may prevent inflammation in vivo by interfering with cellular activation and infiltration. We conclude that cytosolic phospholipase A(2) but not secretory phospholipase A(2) is the predominant enzyme in inflammatory signalling.