Pillinger M H, Capodici C, Rosenthal P, Kheterpal N, Hanft S, Philips M R, Weissmann G
Department of Medicine, Room NB16N1, New York University Medical Center, 550 First Avenue, New York, NY 10016, USA.
Proc Natl Acad Sci U S A. 1998 Nov 24;95(24):14540-5. doi: 10.1073/pnas.95.24.14540.
The anti-inflammatory effects of high-dose salicylates are well recognized, incompletely understood and unlikely due entirely to cyclooxygenase (COX) inhibition. We have previously reported a role for activation of the kinase Erk in CD11b/CD18 integrin-dependent adhesiveness of human neutrophils, a critical step in inflammation. We now report the effects of salicylates on neutrophil Erk and adhesion. Exposure of neutrophils to aspirin or sodium salicylate (poor COX inhibitor) inhibited Erk activity and adhesiveness of formylmethionyl-leucyl-phenylalanine- and arachidonic acid-stimulated neutrophils, consistent with anti-inflammation but not COX inhibition (IC50s = 1-8 mM). In contrast, indomethacin blocked neither Erk nor adhesion. Inhibition of Mek (proximal activator of Erk) also blocked stimulation of Erk and adhesion by formylmethionyl-leucyl-phenylalanineand arachidonic acid. Salicylate inhibition of Erk was independent of protein kinase A activation and generation of extracellular adenosine. These data are consistent with a role for Erk in stimulated neutrophil adhesion, and suggest that anti-inflammatory effects of salicylates may be mediated via inhibition of Erk signaling required for integrin-mediated responses.
高剂量水杨酸盐的抗炎作用已得到充分认可，但尚未完全理解，而且不太可能完全归因于环氧合酶（COX）抑制作用。我们之前报道过激酶Erk的激活在人中性粒细胞的CD11b/CD18整合素依赖性黏附过程中发挥作用，这是炎症中的关键步骤。我们现在报道水杨酸盐对中性粒细胞Erk和黏附的影响。将中性粒细胞暴露于阿司匹林或水杨酸钠（较弱的COX抑制剂）会抑制甲酰甲硫氨酰-亮氨酰-苯丙氨酸和花生四烯酸刺激的中性粒细胞的Erk活性和黏附性，这与抗炎作用相符，但并非COX抑制作用（半数抑制浓度=1-8 mM）。相比之下，吲哚美辛既不阻断Erk也不阻断黏附。抑制Mek（Erk的近端激活剂）也会阻断甲酰甲硫氨酰-亮氨酰-苯丙氨酸和花生四烯酸对Erk的刺激以及黏附。水杨酸盐对Erk的抑制作用独立于蛋白激酶A激活和细胞外腺苷的生成。这些数据与Erk在刺激的中性粒细胞黏附中的作用一致，并表明水杨酸盐的抗炎作用可能是通过抑制整合素介导的反应所需的Erk信号传导来介导的。
