Molecular mechanisms involved in the regulation of cytokine production by muramyl dipeptide
Molecular mechanisms involved in the regulation of cytokine production by muramyl dipeptide
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DOI：
10.1042/bj20061704
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发表时间：
2007-06-01
影响因子：
4.1
通讯作者：
Cohen, Philip
中科院分区：
文献类型：
--
作者：
Windheim, Mark;Lang, Christine;Cohen, Philip
MDP（胞壁酰二肽）是肽聚糖的一种组分，与NOD2（核苷酸结合寡聚化结构域2）相互作用，刺激NOD2-RIP2（受体相互作用蛋白2）复合物，激活对抗菌防御重要的信号通路。在这里，我们证明了RIP2的蛋白激酶活性有两个功能，即限制下游信号的强度和稳定活性酶。因此，用SB 203580 [p38 MAPK（丝裂原活化蛋白激酶）抑制剂]或Src家族激酶抑制剂PP2诱导RIP2蛋白水平的快速和急剧降低，这可能解释了为什么这些RIP2抑制剂阻断MDP刺激的下游信号传导和IL-1 β的产生（白细胞介素-1 β）和TNF α（肿瘤坏死因子-α）。我们还表明，RIP2诱导蛋白激酶TAK1（转化生长因子β激活激酶-1）的激活，TAK1的显性负突变体抑制RIP2诱导的JNK（c-Jun N-末端激酶）和p38 α MAPK的激活，NOD2或RIP2下游的信号传导被TAK1抑制剂（5Z）-7-oxozeaenol或TAK1缺陷细胞减少。我们还表明，MDP激活ERK 1（细胞外信号调节激酶1）/ERK 2和p38 α MAPK在人外周血单核细胞和MAPK和TAK1的活性所需的MDP诱导的信号传导和生产IL-1 β和TNF α在这些细胞。两者合计，我们的研究结果表明，MDP-NOD2/RIP2和LPS（脂多糖）-TLR4（Toll样受体4）信号传导途径收敛于TAK1的水平，并且导致促炎细胞因子产生的许多后续事件是两种途径共同的。
MDP (muramyl dipeptide), a component of peptidoglycan, interacts with NOD2 (nucleotide-binding oligomerization domain 2) stimulating the NOD2-RIP2 (receptor-interacting protein 2) complex to activate signalling pathways important for antibacterial defence. Here we demonstrate that the protein kinase activity of RIP2 has two functions, namely to limit the strength of downstream signalling and to stabilize the active enzyme. Thus pharmacological inhibition of RIP2 kinase with either SB 203580 [a p38 MAPK (mitogen-activated protein kinase) inhibitor] or the Src family kinase inhibitor PP2 induces a rapid and drastic decrease in the level of the RIP2 protein, which may explain why these RIP2 inhibitors block MDP-stimulated downstream signalling and the production of IL-1 beta (interleukin-1 beta) and TNF alpha (tumour necrosis factor-alpha). We also show that RIP2 induces the activation of the protein kinase TAK1 (transforming-growth-factor-beta-activated kinase-1), that a dominant-negative mutant of TAK1 inhibits RIP2-induced activation of JNK (c-Jun N-terminal kinase) and p38 alpha MAPK, and that signalling downstream of NOD2 or RIP2 is reduced by the TAK1 inhibitor (5Z)-7-oxozeaenol or in TAK1-deficient cells. We also show that MDP activates ERK1 (extracellular-signal-regulated kinase 1)/ERK2 and p38 alpha MAPK in human peripheral-blood mononuclear cells and that the activity of both MAPKs and TAK1 are required for MDP-induced signalling and production of IL-1 beta and TNF alpha in these cells. Taken together, our results indicate that the MDP-NOD2/RIP2 and LPS (lipopolysaccharide)-TLR4 (Toll-like receptor 4) signalling pathways converge at the level of TAK1 and that many subsequent events that lead to the production of pro-inflammatory cytokines are common to both pathways.