Liljeroos M, Vuolteenaho R, Morath S, Hartung T, Hallman M, Ojaniemi M
Department of Pediatrics, Biocenter Oulu, P.O. Box 5000, FIN-90014, University of Oulu, Oulu, Finland.
Cell Signal. 2007 Mar;19(3):625-33. doi: 10.1016/j.cellsig.2006.08.013. Epub 2006 Aug 30.
Lipoteichoic acid (LTA) of Gram-positive bacteria initiates innate immune responses via Toll-like receptor-2 (TLR2), resulting in the activation of intracellular signaling and production of inflammatory cytokines in macrophages. Although Bruton's tyrosine kinase (Btk) is biologically important molecule implicated in immune regulation and recently in TLR signaling its importance for LTA-TLR2 mediated responses has not been evaluated. In this study, we detected Btk in the LTA signaling complex with TLR2 and PI 3-kinase (PI3K). The constitutive interaction of these proteins was mediated via PI3K Src homology (SH3) -domain. Both Btk and PI3K were activated by LTA stimulation and the LTA induced cytokine expression was differentially modulated by these kinases. LTA induced the activation of nuclear factor kappaB (NFkappaB), however, only Btk inhibition affected the LTA induced Ser536 phosphorylation and DNA-binding of NFkappaB. In conclusion, our results demonstrate that Btk and PI3K occupy important roles in TLR2-induced activation of macrophages, resulting in selective regulation of cytokines.
革兰氏阳性菌的脂磷壁酸（LTA）通过Toll样受体2（TLR2）引发先天性免疫反应，导致细胞内信号传导激活以及巨噬细胞中炎性细胞因子的产生。尽管布鲁顿酪氨酸激酶（Btk）是参与免疫调节的重要生物学分子，且最近发现其参与TLR信号传导，但尚未评估其在LTA-TLR2介导的反应中的重要性。在本研究中，我们在与TLR2和PI 3-激酶（PI3K）形成的LTA信号复合物中检测到了Btk。这些蛋白质的组成性相互作用是通过PI3K的Src同源（SH3）结构域介导的。Btk和PI3K均被LTA刺激激活，且LTA诱导的细胞因子表达受到这些激酶的差异调节。LTA诱导核因子κB（NFκB）激活，然而，只有抑制Btk会影响LTA诱导的NFκB的Ser536磷酸化和DNA结合。总之，我们的结果表明，Btk和PI3K在TLR2诱导的巨噬细胞激活中起重要作用，从而导致细胞因子的选择性调节。
