CD40 Ligand Binds to α5β1 Integrin and Triggers Cell Signaling.

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作者：

Léveillé，Claire，Bouillon，Marlene，Wen，Guo，Bolduc，Julie，Sharif-Askari，Ehssan

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摘要：

It was originally thought that the critical role of the CD40 ligand (CD40L) in normal and inflammatory immune responses was mainly mediated through its interaction with the classic receptor, CD40. However, data from CD40L-/- and CD40-/- mice suggest that the CD40L-induced inflammatory immune response involves at least one other receptor. This hypothesis is supported by the fact that CD40L stabilizes arterial thrombi through an αIIbβ3-dependent mechanism. Here we provide evidence that soluble CD40L (sCD40L) binds to cells of the undifferentiated human monocytic U937 cell line in a CD40- and αIIbβ3-independent manner. Binding of sCD40L to U937 cells was inhibited by anti-CD40L monoclonal antibody 5C8, anti-α5β1 monoclonal antibody P1D6, and soluble α5β1. The direct binding of sCD40L to purified α5β1 was confirmed in a solid phase binding assay. Binding of sCD40L to α5β1 was modulated by the form of α5β1-expressed on the cell surface as the activation of α5β1 by Mn2+ or dithiothreitol resulted in the loss of sCD40L binding. Moreover, sCD40L induced the translocation of α5β1 to the Triton X-100-insoluble fraction of U937 cells, the rapid activation of the MAPK pathways ERK1/2, and interleukin-8 gene expression. The binding of sCD40L to CD40 on BJAB cells, an α5β1-negative B cell line, and the resulting activation of ERK1/2 was not inhibited by soluble α5β1, suggesting that sCD40L can bind concomitantly to both receptors. These results document the existence of novel CD40L-dependent pathways of physiological relevance for cells expressing multiple receptors (CD40, α5β1, and αIIβ2) for CD40L.

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关键词：

Antibodies, Monoclonal CD40 Ligand Gene Expression Regulation Integrin alpha5beta1 抗体, 单克隆基因表达调控

DOI：

10.1074/jbc.M608342200

被引量：

196

年份：

2007