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Free Content α1β1 integrin and interleukin-7 receptor up-regulate the expression of RANKL in human T cells and enhance their osteoclastogenic function

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Summary

Activated T cells, through the production of the receptor activator of NF-κB ligand (RANKL) cytokine, have been implicated in the osteoclast development and bone loss that are associated with autoimmune diseases such as rheumatoid arthritis. However, the cellular pathways that regulate the expression of RANKL and the induction of osteoclasts are still unclear. In this study, we show that, in human effector CD4+ T cells, activation of α1β1 integrin and interleukin (IL)-7 receptor (IL-7R) up-regulates the expression and production of RANKL but has no effect on the production of interferon-γ, an inhibitor of T-cell-mediated osteoclastogenesis. Thus, both α1β1 integrin and IL-7R enhance the ability of these cells to induce the formation of osteoclasts from human monocytes. Furthermore, we found that simultaneous activation of effector CD4+ T cells via α1β1 integrin and IL-7R synergistically increases the production of RANKL and enhances their osteoclastogenic function. We also show that, although α1β1 integrin does not protect human effector CD4+ T cells from IL-2-withdrawal-induced apoptosis, it does enhance the pro-survival effect of IL-7, further emphasizing the importance of the α1β1/IL-7R synergistic effect. Together our results identify a new function of α1β1 integrin in T cells and suggest that activation of effector CD4+ T cells through α1β1 integrin and IL-7R is an important regulatory pathway in T-cell-dependent osteoclastogenesis. Further understanding of the mechanisms by which IL-7R and α1β1 integrin promote T-cell-mediated osteoclastogenesis will lead to new insights into the regulatory pathways of T-cell-dependent bone resorption associated with autoimmune diseases.
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Keywords: RANKL; effector T cells; integrins; osteoclastogenesis

Document Type: Research Article

Publication date: November 1, 2008

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