Tumour necrosis factor activates the mitogen-activated protein kinases p38alpha and ERK in the synovial membrane in vivo.
Tumour necrosis factor activates the mitogen-activated protein kinases p38alpha and ERK in the synovial membrane in vivo.
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DOI：
10.1186/ar1797
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发表时间：
2005
影响因子：
4.9
通讯作者：
Schett G
中科院分区：
文献类型：
--
作者：
Görtz B;Hayer S;Tuerck B;Zwerina J;Smolen JS;Schett G
肿瘤坏死因子 (TNF) 被认为是慢性滑膜炎症的主要因素，并且是丝裂原激活蛋白激酶 (MAPK) 信号传导的诱导剂。在本研究中，我们研究了 TNF 在体内激活滑膜中 MAPK 的能力。我们研究了人 TNF 转基因小鼠（TNF 诱导的关节炎的体内模型），通过免疫印迹和免疫组织化学检查发炎关节中细胞外信号调节激酶 (ERK)、c-Jun 氨基末端激酶 (JNK) 和 p38MAPKα 的磷酸化。此外，还评估了系统性阻断 TNF、IL-1 和核因子 κB 受体激活剂 (RANK) 配体对 MAPK 激活的影响。在体内，TNF 的过度表达诱导滑膜中 p38MAPKα 和 ERK 的激活，而 JNK 的激活不太明显，并且在免疫组织化学分析中很少观察到。激活的 p38MAPKα 主要存在于滑膜巨噬细胞中，而 ERK 激活则存在于滑膜巨噬细胞和成纤维细胞中。 T 和 B 淋巴细胞未表现出三种 MAPK 中任何一种的主要激活。 TNF 的全身阻断减少了 p38MAPKα 和 ERK 的激活，而 IL-1 的抑制仅影响 p38MAPKα 并且 RANK 配体的阻断不会导致滑膜中 MAPK 激活的任何减少。这些数据表明TNF优先激活暴露于TNF的滑膜中的p38MAPKα和ERK。这不仅表明靶向抑制 p38MAPKα 和 ERK 是阻断 TNF 介导的关节效应的可行策略，而且还表明即使目前可用的阻断 TNF 的方法也能有效减少这两种 MAPK 的激活。
Tumour necrosis factor (TNF) is considered to be a major factor in chronic synovial inflammation and is an inducer of mitogen-activated protein kinase (MAPK) signalling. In the present study we investigated the ability of TNF to activate MAPKs in the synovial membrane in vivo. We studied human TNF transgenic mice – an in vivo model of TNF-induced arthritis – to examine phosphorylation of extracellular signal-regulated kinase (ERK), c-Jun amino terminal kinase (JNK) and p38MAPKα in the inflamed joints by means of immunoblot and immunohistochemistry. In addition, the effects of systemic blockade of TNF, IL-1 and receptor activator of nuclear factor-κB (RANK) ligand on the activation of MAPKs were assessed. In vivo, overexpression of TNF induced activation of p38MAPKα and ERK in the synovial membrane, whereas activation of JNK was less pronounced and rarely observed on immunohistochemical analysis. Activated p38MAPKα was predominantly found in synovial macrophages, whereas ERK activation was present in both synovial macrophages and fibroblasts. T and B lymphocytes did not exhibit major activation of any of the three MAPKs. Systemic blockade of TNF reduced activation of p38MAPKα and ERK, whereas inhibition of IL-1 only affected p38MAPKα and blockade of RANK ligand did not result in any decrease in MAPK activation in the synovial membrane. These data indicate that TNF preferentially activates p38MAPKα and ERK in synovial membrane exposed to TNF. This not only suggests that targeted inhibition of p38MAPKα and ERK is a feasible strategy for blocking TNF-mediated effects on joints, but it also shows that even currently available methods to block TNF effectively reduce activation of these two MAPKs.
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影响因子：
3.7
作者：
Liacini, A;Sylvester, J;Zafarullah, M
通讯作者：
Zafarullah, M
影响因子：
--
作者：
Nishikawa, M;Myoui, A;Yoshikawa, H
通讯作者：
Yoshikawa, H
影响因子：
56.9
作者：
Johnson, GL;Lapadat, R
通讯作者：
Lapadat, R
影响因子：
11.4
作者：
KEFFER, J;PROBERT, L;KOLLIAS, G
通讯作者：
KOLLIAS, G
影响因子：
12.4
作者：
Schett, G;Steiner, CW;Steiner, G
通讯作者：
Steiner, G