A Chemotactic Peptide from Laminin α5 Functions as a Regulator of Inflammatory Immune Responses via TNFα-mediated Signaling1
A Chemotactic Peptide from Laminin α5 Functions as a Regulator of Inflammatory Immune Responses via TNFα-mediated Signaling1
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来自层粘连蛋白 α5 的趋化肽通过 TNFα 介导的信号传导发挥炎症免疫反应的调节作用1
作者：
T. Adair;J. Atkinson;D. Kelley;R. Arch;J. Miner;R. Senior
组织损伤触发炎症反应，可能导致降解产物的释放或细胞外基质成分的隐蔽结构域暴露。此前，我们已经证明，层粘连蛋白-10(α-10，α5β1γ1)链中的一个隐含肽(AQARSAASKVKVSMKF)对中性粒细胞(PMN)和巨噬细胞(MφS)都具有趋化作用，并诱导基质金属蛋白酶-9(MMP9)的产生。为了确定AQARSAASKVKVSMKF是否对炎症细胞有额外的作用，我们对AQARSAASKVKVSMKF刺激的RAW264.7MφS进行了基因芯片分析。几种细胞因子和细胞因子受体对层粘连蛋白α5肽的反应增加了3倍。其中包括肿瘤坏死因子-α及其受体之一的p75TNFR(TNFR-II)，分别增加了3.5倍和5.7倍。但该多肽对p55TNFR(TNFR-I)的表达无影响。基因芯片数据证实，AQARSAASKVKVSMKF刺激RAW264.7细胞后，肿瘤坏死因子-α和肿瘤坏死因子受体-II的蛋白水平增加。此外，我们还确定AQARSAASKVKVSMKF对肿瘤坏死因子-α和肿瘤坏死因子受体-II的产生先于基质金属蛋白酶-9的产生。此外，利用肿瘤坏死因子受体-I和/或肿瘤坏死因子受体-II缺陷小鼠的原代M-φS，我们确定AQARSAASKVKVSMKF通过一条由肿瘤坏死因子受体-II触发的通路诱导M-αS表达φ-9。然而，肿瘤坏死因子-α信号不是AQARSAASKVKVSMKF诱导的中性粒细胞释放基质金属蛋白酶-9或中性粒细胞迁移所必需的。这些数据表明，炎症细胞与基底膜成分的相互作用可能通过诱导细胞因子的表达、炎症细胞的募集和蛋白水解酶的释放来协调免疫反应。
Tissue injury triggers inflammatory responses that may result in release of degradation products or exposure of cryptic domains of extracellular matrix components. Previously, we have shown that a cryptic peptide (AQARSAASKVKVSMKF) in the α-chain of laminin-10 (α5β1γ1), a prominent basement membrane component, is chemotactic for both neutrophils (PMNs) and macrophages (Mφs) and induces matrix metalloproteinase-9 (MMP-9) production. To determine whether AQARSAASKVKVSMKF has additional effects on inflammatory cells, we performed microarray analysis of RNA from RAW264.7 Mφs stimulated with AQARSAASKVKVSMKF. Several cytokines and cytokine receptors were increased >3-fold in response to the laminin α5 peptide. Among these were TNF-α and one of its receptors, the p75 TNFR (TNFR-II), increasing 3.5- and 5.7-fold, respectively. However, the peptide had no effect on p55 TNFR (TNFR-I) expression. Corroborating the microarray data, the protein levels of TNF-α and TNFR-II were increased following stimulation of RAW264.7 cells with AQARSAASKVKVSMKF. In addition, we determined that the production of TNF-α and TNFR-II in response to AQARSAASKVKVSMKF preceded the production of MMP-9. Furthermore, using primary Mφs from mice deficient in TNFR-I, TNFR-II, or both TNF-α receptors (TNFRs), we determined that AQARSAASKVKVSMKF induces MMP-9 expression by Mφs through a pathway triggered by TNFR-II. However, TNF-α signaling is not required for AQARSAASKVKVSMKF-induced PMN release of MMP-9 or PMN emigration. These data suggest that interactions of inflammatory cells with basement membrane components may orchestrate immune responses by inducing expression of cytokines, recruitment of inflammatory cells, and release of proteinases.
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