Tumor necrosis factor and CD11/CD18 (beta 2) integrins act synergistically to lower cAMP in human neutrophils.
Tumor necrosis factor and CD11/CD18 (beta 2) integrins act synergistically to lower cAMP in human neutrophils.
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DOI：
10.1083/jcb.111.5.2171
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发表时间：
1990-11
期刊：
影响因子：
--
通讯作者：
Sanchez E
中科院分区：
文献类型：
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作者：
Nathan C;Sanchez E
中性粒细胞 (PMN) 响应肿瘤坏死因子-α (TNF) 等细胞因子而经历长时间呼吸爆发的能力取决于 CD11/CD18 (β 2) 整合素的表达以及与基质蛋白包被表面的相互作用（Nathan, C.、S. Srimal、C. Farber、E. Sanchez、L. Kabbash、A. Asch、J. Gailit 和 S. D. Wright. 1989。 J.细胞生物学。109：1341-1349）。我们测试了 cAMP 的变化介导细胞因子和整合素的联合作用的假设。当铺在 FBS 或纤维蛋白原包被的表面上时，PMN 对 TNF 做出反应，导致细胞内 cAMP 持续下降。如果没有 TNF，这种情况就不会发生；悬浮 PMN 中；在用抗 CD18 mAb 治疗的 PMN 中；或 PMN 中 β2 整合素遗传缺陷。 cAMP 的先前下降似乎对于 TNF 诱导呼吸爆发至关重要，因为如果在呼吸爆发之前（而不是之后）任何时间添加升高 cAMP 的药物，则可以阻止呼吸爆发。如果在 TNF 诱导的呼吸爆发之前而非之后添加，腺苷类似物和细胞松弛素也能阻止其发生。两者还可以阻止 TNF 诱导的 cAMP 下降。细胞松弛素的作用促使我们研究 cAMP 和肌动蛋白重组之间的关系。导致 cAMP 持续下降的相同条件同时导致细胞扩散和肌动蛋白丝的组装。与呼吸爆发一样，如果在扩散开始之前而非之后添加，cAMP 升高剂会抑制 TNF 诱导的细胞扩散和肌动蛋白丝组装。因此，TNF 受体的占据和 CD18 整合素的参与在 PMN 中协同相互作用，促进 cAMP 下降。 cAMP的下降与细胞扩散和肌动蛋白重组密切相关。这些变化对于 TNF 诱导长时间呼吸爆发是必要的。我们得出的结论是，整合素可以与细胞因子共同作用，通过改变第二信使 cAMP 的水平来影响细胞的形状和功能。
The ability of neutrophils (PMN) to undergo a prolonged respiratory burst in response to cytokines such as tumor necrosis factor-alpha (TNF) depends on expression of CD11/CD18 (beta 2) integrins and interaction with matrix protein-coated surfaces (Nathan, C., S. Srimal, C. Farber, E. Sanchez, L. Kabbash, A. Asch, J. Gailit, and S. D. Wright. 1989. J. Cell Biol. 109:1341-1349). We tested the hypothesis that changes in cAMP mediate the joint action of cytokines and integrins. When plated on FBS- or fibrinogen-coated surfaces, PMN responded to TNF with a sustained fall in intracellular cAMP. This did not occur without TNF; in suspended PMN; in PMN treated with anti-CD18 mAb; or in PMN genetically deficient in beta 2 integrins. A preceding fall in cAMP appeared essential for TNF to induce a respiratory burst, because drugs that elevate cAMP blocked the burst if added any time before, but not after, its onset. Adenosine analogues and cytochalasins also block the TNF-induced respiratory burst if added before, but not after, its onset. Both also blocked the TNF-induced fall in cAMP. The effect of cytochalasins led us to examine the relationship between cAMP and actin reorganization. The same conditions that led to a sustained fall in cAMP led at the same time to cell spreading and the assembly of actin filaments. As with the respiratory burst, cAMP-elevating agents inhibited TNF-induced cell spreading and actin filament assembly if added before, but not after, spreading began. Thus, occupation of TNF receptors and engagement of CD18 integrins interact synergistically in PMN to promote a fall in cAMP. The fall in cAMP is closely related to cell spreading and actin reorganization. These changes are necessary for TNF to induce a prolonged respiratory burst. We conclude that integrins can act jointly with cytokines to affect cell shape and function through alterations in the level of a second messenger, cAMP.