A site on laminin α5, AQARSAASKVKVSMKF, induces inflammatory cell production of matrix metalloproteinase-9 and chemotaxis
A site on laminin α5, AQARSAASKVKVSMKF, induces inflammatory cell production of matrix metalloproteinase-9 and chemotaxis
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DOI：
10.4049/jimmunol.171.1.398
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发表时间：
2003-07-01
影响因子：
4.4
通讯作者：
Senior, RM
中科院分区：
文献类型：
--
作者：
Adair-Kirk, TL;Atkinson, JJ;Senior, RM
层粘连蛋白(Ln)-1的α链——层粘连蛋白α -1中的几个肽序列在体外介导生物反应，但Ln-1在体内很少见。由于Ln-5和Ln-10分别含有α 3和α 5链，是正常成人组织中最突出的层粘连蛋白异源三聚体，而其他层粘连蛋白链的功能域很少，因此我们正在研究α 3和α 5链的生物活性。层粘连蛋白α 5肽AQARSAASKVKYSMKF在条件培养基中孵育小鼠巨噬细胞，导致基质金属蛋白酶(MMP)-9 mRNA和明胶溶解活性显著增加，而相应的α 3肽QQARDAANKVAIPMRF则没有影响。AQARSAASKVKVSMKF也诱导了MMP-14的表达，而MMP-2、MMP-3、mmp -7、MMP-12和MMP-13不受该肽的诱导。缺失分析表明ASKVKVSMKF的最小序列足以增加MMP-9的表达。AQARSAASKVKVSMKF在体外也对中性粒细胞和巨噬细胞具有趋化作用，并在小鼠鼻内滴入后诱导中性粒细胞和巨噬细胞在体内肺间隙积聚。在MMP-9缺陷小鼠中也发生了类似的积累，这表明MMP-9不是aqarsaaskvkvsmkf诱导的肺炎症细胞迁移所必需的。最小肽的打乱版本KAKSFVMVSK没有活性。这些数据表明，层粘连蛋白α 5衍生肽可以诱导炎症细胞趋化性和金属蛋白酶活性。
Several peptide sequences in laminin alpha1, the alpha-chain of laminin (Ln)-1, mediate biological responses in vitro, but Ln-1 is rare in vivo. Since Ln-5 and Ln-10, which contain the alpha3 and alpha5 chains, respectively, are the most prominent laminin heterotrimers in normal adult tissues and few functional domains in other laminin chains have been identified, we are investigating the alpha3 and alpha5 chains for biological activities. Incubation of mouse macrophages with the laminin alpha5 peptide AQARSAASKVKYSMKF resulted in marked increase in matrix metalloproteinase (MMP)-9 mRNA and gelatinolytic activity in the conditioned media, whereas the corresponding alpha3 peptide QQARDAANKVAIPMRF had no effect. AQARSAASKVKVSMKF also induced expression of MMP-14, while MMP-2, MMP-3, MNP-7, MMP-12, and MMP-13 were not induced by this peptide. Deletion analyses indicated that a minimal sequence of ASKVKVSMKF was sufficient for increasing MMP-9 expression. AQARSAASKVKVSMKF was also chemotactic for neutrophils and macrophages in vitro, and induced accumulation of neutrophils and macrophages in lung airspaces in vivo following intranasal instillation into mice. Comparable accumulation occurred in MMP-9-deficient mice, indicating that MMP-9 was not required for AQARSAASKVKVSMKF-induced inflammatory cell emigration in the lung. A scrambled version of the minimal peptide, KAKSFVMVSK, was inactive. These data indicate that laminin alpha5-derived peptides can induce inflammatory cell chemotaxis and metalloproteinase activity.