Tumor necrosis factor-alpha (TNF-α) induces integrin CD11b/CD18 (Mac-1) up-regulation and migration to the CC chemokine CCL3 (MIP-1α) on human neutrophils through defined signalling pathways
Tumor necrosis factor-alpha (TNF-α) induces integrin CD11b/CD18 (Mac-1) up-regulation and migration to the CC chemokine CCL3 (MIP-1α) on human neutrophils through defined signalling pathways
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DOI：
10.1016/j.cellsig.2007.11.008
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发表时间：
2008-03-01
影响因子：
4.8
通讯作者：
Ottonello, Luciano
中科院分区：
文献类型：
--
作者：
Montecucco, Fabrizio;Steffens, Sabine;Ottonello, Luciano
强有力的证据表明，中性粒细胞可能在急性和慢性炎症性疾病，如类风湿关节炎和动脉粥样硬化中发挥积极作用。考虑到促炎细胞因子tnf - α在这些炎症过程中的作用，我们计划进行本研究，研究tnf - α短期孵育对中性粒细胞向CCL3迁移的影响，CCL3是炎症部位产生的一种趋化因子，通常缺乏中性粒细胞趋化特性。我们发现tnf - α引发中性粒细胞通过CCR5迁移到CCL3。tnf - α诱导的迁移是tnf - α诱导的中性粒细胞表面整合素CD11b/CD18 （Mac-1）上调的结果。此外，研究发现tnf - α活性严格依赖于ERK 1/2 p44的激活，并与Src激酶、PI3K/Akt、p38 MAPK等细胞内通路合作，这些通路在经典化学吸引剂（CXCL8）或引物剂（GM-CSF）的作用下被激活。相反，tnf - α对中性粒细胞向CCL3迁移的影响不依赖于jnk1 /2。总之，本报告表明，tnf - α揭示了中性粒细胞通过Mac-1的干预向CCL3迁移的一种以前未知的能力。tnf - α通过信号通路调节Mac-1上调，涉及多种激酶，但不包括jnk1 /2。尽管高度推测，ERK 1/2 p44可能是tnf - α介导的炎症状态中中性粒细胞介导的不良活动的药理学操纵的选择性靶标。(C) 2007爱思唯尔公司版权所有。
Strong evidence suggests that neutrophils may play an active role in acute and chronic inflammatory disorders, such as rheumatoid arthritis and atherosclerosis. Given the role of pro-inflammatory cytokine TNF-alpha in these inflammatory processes, we planned the present study to investigate the effect of short term incubation with TNF-alpha on neutrophil migration to CCL3, a chemokine produced in inflammatory sites and normally devoid of neutrophil chemotactic properties. We found that TNF-alpha primed neutrophils for migration to CCL3 via CCR5. TNF-alpha-induced migration was a consequence of the TNF-alpha-induced up-regulation of integrin CD11b/CD18 (Mac-1) on neutrophil surface. Furthermore, TNF-alpha activity was found to be strictly dependent on the activation of ERK 1/2 p44, cooperating with the intracellular pathways involving Src kinases, PI3K/Akt, p38 MAPK, well known as activated in response to classical chemoattractants (CXCL8) or priming agents (GM-CSF). On the contrary, the effect of TNF-alpha on neutrophil migration to CCL3 was not dependent on JNK 1/2. In conclusion, the present report shows that TNF-alpha unveils a previously unknown capacity of neutrophils to migrate to CCL3 through the intervention of Mac-1. TNF-alpha regulates Mac-1 up-regulation through signalling pathways, involving various kinases, but not JNK 1/2. Although highly speculative, ERK 1/2 p44 may represent a selective target for the pharmacologic manipulation of neutrophil-mediated adverse activities in TNF-alpha-mediated inflammatory states. (C) 2007 Elsevier Inc. All rights reserved.