IL-10 suppresses calcium-mediated costimulation of receptor activator NF-kappa B signaling during human osteoclast differentiation by inhibiting TREM-2 expression.
IL-10 suppresses calcium-mediated costimulation of receptor activator NF-kappa B signaling during human osteoclast differentiation by inhibiting TREM-2 expression.
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DOI：
10.4049/jimmunol.0804165
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发表时间：
2009-08-15
期刊：
影响因子：
--
通讯作者：
Ivashkiv LB
中科院分区：
文献类型：
--
作者：
Park-Min KH;Ji JD;Antoniv T;Reid AC;Silver RB;Humphrey MB;Nakamura M;Ivashkiv LB
RANK有效诱导破骨细胞生成需要ITAM偶联受体的共刺激。在人类中，TREM-2 ITAM偶联受体在骨重建中起关键作用，因为TREM-2突变患者表现出破骨细胞生成缺陷和骨病变。我们已经确定了一种新的快速诱导的RANK信号转导共刺激途径，该途径依赖于TREM-2并由钙信号转导介导。TREM-2依赖性钙信号是RANK介导的CaMKII和下游MEK和ERK MAPK活化所必需的，这对破骨细胞生成很重要。IL-10抑制RANK诱导的破骨细胞生成，并通过抑制TREM-2的转录选择性抑制RANK下游的钙信号传导。TREM-2表达下调导致RANKL诱导的CaMK-MEK-ERK通路活化减少，破骨细胞生成主调节因子NFATc 1表达减少。这些发现为抑制人破骨细胞分化提供了新的机制。这些结果还深入了解了ITAM偶联受体和异源受体（如RANK）之间的串扰，并确定了IL-10抑制细胞对TNFR家族成员反应的机制。
Induction of effective osteoclastogenesis by RANK requires costimulation by ITAM-coupled receptors. In humans, the TREM-2 ITAM-coupled receptor plays a key role in bone remodeling, as patients with TREM-2 mutations exhibit defective osteoclastogenesis and bone lesions. We have identified a new rapidly induced costimulatory pathway for RANK signaling that is dependent on TREM-2 and mediated by calcium signaling. TREM-2-dependent calcium signals are required for RANK-mediated activation of CaMKII and downstream MEK and ERK MAPKs that are important for osteoclastogenesis. IL-10 inhibited RANK-induced osteoclastogenesis and selectively inhibited calcium signaling downstream of RANK by inhibiting transcription of TREM-2. Downregulation of TREM-2 expression resulted in diminished RANKL-induced activation of the CaMK-MEK-ERK pathway and decreased expression of the master regulator of osteoclastogenesis NFATc1. These findings provide a new mechanism of inhibition of human osteoclast differentiation. The results also yield insights into crosstalk between ITAM-coupled receptors and heterologous receptors such as RANK, and identify a mechanism by which IL-10 can suppress cellular responses to TNFR family members.
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DOI：
10.1084/jem.190.12.1741
发表时间：
1999-12-20
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Arai F;Miyamoto T;Ohneda O;Inada T;Sudo T;Brasel K;Miyata T;Anderson DM;Suda T
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Suda T
影响因子：
5.3
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Faccio, Roberta
影响因子：
4.4
作者：
Hamerman, Jessica A.;Jarjoura, Vessica R.;Lanier, Lewis L.
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Lanier, Lewis L.
DOI：
10.1073/pnas.0401602101
发表时间：
2004-04-20
影响因子：
11.1
作者：
Mócsai, A;Humphrey, MB;Nakamura, MC
通讯作者：
Nakamura, MC
DOI：
10.1016/j.bbrc.2005.07.092
发表时间：
2005-09-23
影响因子：
3.1
作者：
Kwon, OH;Lee, CK;Lee, HJ
通讯作者：
Lee, HJ