Interleukin-4 reversibly inhibits osteoclastogenesis via inhibition of NF-κB and mitogen-activated protein kinase signaling
Interleukin-4 reversibly inhibits osteoclastogenesis via inhibition of NF-κB and mitogen-activated protein kinase signaling
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DOI：
10.1074/jbc.m104957200
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发表时间：
2002-02-22
影响因子：
4.8
通讯作者：
Ross, FP
中科院分区：
文献类型：
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作者：
Wei, S;Wang, MWH;Ross, FP
为了确定白细胞介素（IL）-4可逆地抑制骨髓巨噬细胞（BMSCs）形成破骨细胞（OC）的分子机制，我们检测了这种T细胞衍生的细胞因子影响已知调节破骨细胞生成的信号的能力，这些信号包括由巨噬细胞集落刺激因子（M-CSF）、活化NF-κ B配体的受体（RANKL）、肿瘤坏死因子（TNF）、和IL-1我们发现，虽然用IL-4预处理Bcefe不会改变M-CSF信号，但它可逆地阻断了NF-κ B、JNK、p38和ERK信号的RANKL依赖性激活。IL-4还选择性地抑制TNF信号传导，同时增强IL-1的信号传导。与以前的报道相反，我们发现MEK抑制剂剂量依赖性地抑制OC分化。为了鉴定介导IL-4抑制OC形成的更近端信号，我们使用了缺乏STAT 6或SHIP 1的小鼠，这两种衔接蛋白结合IL-4受体。IL-4不能抑制RANKL/M-CSF诱导的破骨细胞生成，这是由STAT 6基因敲除小鼠而不是SHIP 1基因敲除小鼠产生的BCL 4引起的。与此观察结果一致，IL-4对RANKL诱导的NF-κ B和丝裂原活化蛋白激酶活化的抑制作用是STAT 6依赖性的。我们的结论是，IL-4可逆地阻止破骨细胞的生成，以STAT 6依赖的方式1）防止LkappaB磷酸化，从而NF-κ B激活，2）阻断JNK，p38，ERK丝裂原活化蛋白激酶途径。
To define the molecular mechanism(s) by which interleukin (IL)-4 reversibly inhibits formation of osteoclasts (OCs) from bone marrow macrophages (BMMs), we examined the capacity of this T cell-derived cytokine to impact signals known to modulate osteoclastogenesis, which include those initiated by macrophage colony-stimulating factor (M-CSF), receptor for activation of NF-kappaB ligand (RANKL), tumor necrosis factor (TNF), and IL-1. We find that although pretreatment of BMMs with IL-4 does not alter M-CSF signaling, it reversibly blocks RANKL-dependent activation of the NF-kappaB, JNK, p38, and ERK signals. IL-4 also selectively inhibits TNF signaling, while enhancing that of IL-1. Contrary to previous reports, we find that MEK inhibitors dose-dependently inhibit OC differentiation. To identify more proximal signals mediating inhibition of OC formation by IL-4, we used mice lacking STAT6 or SHIP1, two adapter proteins that bind the IL-4 receptor. IL-4 fails to inhibit RANKL,/M-CSF-induced osteoclastogenesis by BMMs derived from STAT6-, but not SHIP1-, knockout mice. Consistent with this observation, the inhibitory effects of IL-4 on RANKL-induced NF-kappaB and mitogen-activated protein kinase activation are STAT6-dependent. We conclude that IL-4 reversibly arrests osteoclastogenesis in a STAT6-dependent manner by 1) preventing LkappaB phosphorylation and thus NF-kappaB activation, and 2) blockade of the JNK, p38, and ERK mitogen-activated protein kinase pathways.