Peptidoglycan and lipopolysaccharide activate PLCγ2, leading to enhanced cytokine production in macrophages and dendritic cells
Peptidoglycan and lipopolysaccharide activate PLCγ2, leading to enhanced cytokine production in macrophages and dendritic cells
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DOI：
10.1111/j.1365-2443.2007.01159.x
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发表时间：
2008-02-01
期刊：
影响因子：
2.1
通讯作者：
Yoshimura, Akihiko
中科院分区：
文献类型：
--
作者：
Aki, Daisuke;Minoda, Yasumasa;Yoshimura, Akihiko
在巨噬细胞和单核细胞中，微生物组分通过Toll样受体（TLR）触发促炎细胞因子的产生。尽管主要的TLR信号传导途径由丝氨酸/苏氨酸激酶（包括TAK 1、IKK和MAP激酶）介导，但在许多报道中已经提出了TLR配体对细胞内蛋白的酪氨酸磷酸化。在这里，我们证明了革兰氏阳性细菌细胞壁组分的肽聚糖（PGN）、革兰氏阳性细菌组分的TLR 2配体和脂多糖（LPS）、TLR 4配体诱导磷脂酶C γ 2（PLC γ 2）的酪氨酸磷酸化，导致骨髓源性巨噬细胞（BMM phi）和骨髓源性树突状细胞（BMDC）中的细胞内游离Ca 2+动员。在PLC gamma 2基因敲除小鼠的BMDC中未观察到PGN和LPS诱导的Ca 2+动员。因此，PLC γ 2对于TLR 2和TLR 4介导的Ca 2+通量是必需的。在PLC γ 2-敲低细胞中，PGN诱导的I κ B-α磷酸化和p38活化减少。此外，PLC γ 2对于TNF-α和IL-6的充分产生是必要的。这些数据表明PLC γ 2途径在细菌配体诱导的巨噬细胞和树突状细胞的活化中起重要作用。
In macrophages and monocytes, microbial components trigger the production of pro-inflammatory cytokine through Toll-like receptors (TLRs). Although major TLR signaling pathways are mediated by serine/threonine kinases, including TAK1, IKK and MAP kinases, tyrosine phosphorylation of intracellular proteins by TLR ligands has been suggested in a number of reports. Here, we demonstrated that peptidoglycan (PGN) of a Gram-positive bacterial cell wall component, a TLR2 ligand and lipopoysaccharide (LPS) of a Gram-positive bacterial component, a TLR4 ligand induced tyrosine phosphorylation of phospholipase C gamma-2 (PLC gamma 2), leading to intracellular free Ca2+ mobilization in bone marrow-derived macrophages (BMM phi) and bone marrow-derived dendritic cells (BMDC). PGN- and LPS-induced Ca2+ mobilization was not observed in BMDC from PLC gamma 2 knockout mice. Thus, PLC gamma 2 is essential for TLR2 and TLR4-mediated Ca2+ flux. In PLC gamma 2-knockdown cells, PGN-induced I kappa B-alpha phosphorylation and p38 activation were reduced. Moreover, PLC gamma 2 was necessary for the full production of TNF-alpha and IL-6. These data indicate that the PLC gamma 2 pathway plays an important role in bacterial ligands-induced activation of macrophages and dendritic cells.