Cbl-b is a negative regulator of inflammatory cytokines produced by IgE-activated mast cells
Cbl-b is a negative regulator of inflammatory cytokines produced by IgE-activated mast cells
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DOI：
10.4049/jimmunol.177.9.5980
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发表时间：
2006-11-01
影响因子：
4.4
通讯作者：
Langdon, Wallace Y.
中科院分区：
文献类型：
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作者：
Gustin, Sonja E.;Thien, Christine B. F.;Langdon, Wallace Y.
C-Cb1和Cbl-bE3泛素连接酶在造血细胞中大量表达，它们负向调节许多细胞表面受体和相关信号分子的活性和水平。通过比较c-Cbl和Cbl-b缺陷小鼠骨髓来源的肥大细胞，最近发现Cbl-b是负调控高亲和力IgE受体信号反应的主要家族成员。在本研究中，我们认为Cbl-b基因缺陷小鼠的IgE受体信号转导增强的一个可能原因是肥大细胞中Cbl-b蛋白的相对水平高于其他造血细胞。我们还直接比较了c-Cbl和Cbl-b缺陷小鼠的肥大细胞，发现Cbl-b的丢失，而不是c-Cbl的丢失，促进了细胞生长，延缓了受体内化，并导致Syk及其底物的持续酪氨酸磷酸化。然而，Cbl-b的丢失不会增强ERK或Akt的激活，也不会促进更大的钙反应。此外，Cbl-b或c-Cbl的缺失不会增加Syk或Lyn蛋白酪氨酸激酶的水平。然而，最值得注意的是，与c-Cbl(-/-)或野生型细胞相比，CBI-b(-/-)肥大细胞产生的促炎细胞因子TNF-α、IL-6和MCP-1的水平有极大的增加。这种明显的诱导，似乎受限于这三种细胞因子，依赖于IgE受体的激活，并与增强的licB激酶磷酸化相关。因此，Cbl-b对促进过敏和炎症反应的细胞因子起着强有力的负调节作用。
c-Cbl and Cbl-b E3 ubiquitin ligases are abundantly expressed in hemopoietic cells where they negatively regulate the activity and levels of many cell surface receptors and associated signaling molecules. By comparing bone marrow-derived mast cells from c-Cbl and Cbl-b-deficient mice it has recently been shown that Cbl-b is the dominant family member for negatively regulating signaling responses from high-affinity IgE receptors. In this study, we suggest that a possible reason for the greater enhancement of IgE receptor signaling in Cbl-b-deficient mice is the relatively higher levels of Cbl-b protein over c-Cbl in mast cells compared with other hemopoietic cells. We also directly compare mast cells from c-Cbl and Cbl-b-deficient mice and find that loss of Cbl-b, but not c-Cbl, increases cell growth, retards receptor internalization, and causes the sustained tyrosine phosphorylation of Syk and its substrates. However, loss of Cbl-b does not enhance the activation of ERK or Akt, nor does it promote a greater calcium response. Furthermore, loss of Cbl-b or c-Cbl does not increase levels of the Syk or Lyn protein tyrosine kinases. Most notable, however, is the extremely large increase in the production of proinflammatory cytokines TNF-alpha, IL-6, and MCP-1 by Cbi-b(-/-)mast cells compared with levels produced by c-Cbl(-/-) or wild-type cells. This marked induction, which appears to be restricted to these three cytokines, is dependent on IgE receptor activation and correlates with enhanced licB kinase phosphorylation. Thus, Cbl-b functions as a potent negative regulator of cytokines that promote allergic and inflammatory reactions.