Division of Molecular Immunology, Cincinnati Children's Hospital Research Foundation, Cincinnati, OH 45229, USA.
J Immunol. 2012 Mar 1;188(5):2065-9. doi: 10.4049/jimmunol.1103282. Epub 2012 Jan 30.
Mechanistic understanding of RP105 has been confounded by the fact that this TLR homolog has appeared to have opposing, cell type-specific effects on TLR4 signaling. Although RP105 inhibits TLR4-driven signaling in cell lines and myeloid cells, impaired LPS-driven proliferation by B cells from RP105(-/-) mice has suggested that RP105 facilitates TLR4 signaling in B cells. In this article, we show that modulation of B cell proliferation by RP105 is not a function of B cell-intrinsic expression of RP105, and identify a mechanistic role for dysregulated BAFF expression in the proliferative abnormalities of B cells from RP105(-/-) mice: serum BAFF levels are elevated in RP105(-/-) mice, and partial BAFF neutralization rescues aberrant B cell proliferative responses in such mice. These data indicate that RP105 does not have dichotomous effects on TLR4 signaling and emphasize the need for caution in interpreting the results of global genetic deletion.
对 RP105 的机制理解受到了干扰，因为这种 TLR 同源物似乎对 TLR4 信号具有相反的、细胞类型特异性的影响。虽然 RP105 在细胞系和髓样细胞中抑制 TLR4 驱动的信号，但来自 RP105(-/-)小鼠的 B 细胞中 LPS 驱动的增殖受损表明 RP105促进了 B 细胞中的 TLR4 信号。在本文中，我们表明，RP105 对 B 细胞增殖的调节不是 RP105 内在表达的功能，并且确定了 BAFF 表达失调在 RP105(-/-)小鼠中 B 细胞增殖异常中的作用机制：RP105(-/-)小鼠中的血清 BAFF 水平升高，并且部分 BAFF 中和可挽救此类小鼠中异常的 B 细胞增殖反应。这些数据表明，RP105 对 TLR4 信号没有二分法的影响，并强调在解释全局基因缺失的结果时需要谨慎。
