Gerli R, Paolucci C, Gresele P, Bistoni O, Fiorucci S, Muscat C, Belia S, Bertotto A, Costantini V
Institute of Internal Medicine and Oncological Sciences, Center for the Study of Rheumatic Diseases, Perugia, Italy.
Blood. 1998 Oct 1;92(7):2389-98.
The inhibition of cyclooxygenase does not fully account for the spectrum of activities of nonsteroidal antiinflammatory drugs. It is evident, indeed, that regulation of inflammatory cell function may contribute in explaining some of the effects of these drugs. Tissue recruitment of T cells plays a key role in the development of chronic inflammation. Therefore, the effects of salicylates on T-cell adhesion to and migration through endothelial cell monolayers on collagen were analyzed in an in vitro static system. Aspirin and sodium salicylate reduced the ability of unstimulated T cells to adhere to and transmigrate through cytokine-activated endothelium. Although salicylates did not modify the expression of integrins on T cells, they blunted the increased adherence induced by the anti-beta2 monoclonal antibody (MoAb) KIM127 and prevented the appearance of an activation-dependent epitope of the CD11/CD18 complex, recognized by the MoAb 24, induced by contact with endothelial cells. Salicylates also induced an increase of intracellular calcium ([Ca2+]i) and activation of protein kinase C (PKC) in T cells, but not cell proliferation and interleukin (IL)-2 synthesis. The reduction of T-cell adhesiveness appears to be dependent on the increase in[Ca2+]i levels, as it could be reversed by blocking Ca2+ influx, but not by inhibiting PKC. Moreover, ionomycin at concentrations giving an increase in [Ca2+]i similar to that triggered by aspirin, strictly reproduced the T-cell phenotypic and functional changes induced by salicylates. Aspirin reduced T-cell adhesion and migration also ex vivo after infusion to healthy volunteers. These data suggest that the antiinflammatory activity of salicylates may be due, at least in part, to an interference with the integrin-mediated binding of resting T lymphocytes to activated endothelium with consequent reduction of a specific T-cell recruitment into inflammatory sites.
环氧化酶的抑制作用并不能完全解释非甾体抗炎药的活性谱。实际上，很明显炎症细胞功能的调节可能有助于解释这些药物的一些作用。T细胞向组织的募集在慢性炎症的发展中起关键作用。因此，在体外静态系统中分析了水杨酸盐对T细胞与内皮细胞单层在胶原蛋白上的黏附及迁移的影响。阿司匹林和水杨酸钠降低了未刺激的T细胞黏附于细胞因子激活的内皮细胞并穿过内皮细胞单层迁移的能力。尽管水杨酸盐没有改变T细胞上整合素的表达，但它们减弱了抗β2单克隆抗体（MoAb）KIM127诱导的黏附增加，并阻止了由与内皮细胞接触诱导的、被MoAb 24识别的CD11/CD18复合物的活化依赖性表位的出现。水杨酸盐还诱导T细胞内钙（[Ca2+]i）增加和蛋白激酶C（PKC）活化，但不影响细胞增殖和白细胞介素（IL）-2合成。T细胞黏附性的降低似乎依赖于[Ca2+]i水平的升高，因为阻断Ca2+内流可使其逆转，但抑制PKC则不能。此外，离子霉素在能使[Ca2+]i升高至与阿司匹林引发的升高相似水平的浓度下，严格重现了水杨酸盐诱导的T细胞表型和功能变化。对健康志愿者输注阿司匹林后，其在体内外也降低了T细胞黏附和迁移。这些数据表明，水杨酸盐的抗炎活性可能至少部分归因于对静息T淋巴细胞与活化内皮细胞整合素介导结合的干扰，从而减少特定T细胞向炎症部位的募集。
