SOCS-3 negatively regulates innate and adaptive immune mechanisms in acute IL-1-dependent inflammatory arthritis
SOCS-3 negatively regulates innate and adaptive immune mechanisms in acute IL-1-dependent inflammatory arthritis
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DOI：
10.1172/jci25660
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发表时间：
2006-06-01
影响因子：
15.9
通讯作者：
Wicks, Ian P.
中科院分区：
文献类型：
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作者：
Wong, Peter K. K.;Egan, Paul J.;Wicks, Ian P.
类风湿关节炎是一种自身免疫性疾病，其特征是促炎和抗炎免疫机制之间的持续失衡。SOCS蛋白是细胞因子信号传导的负调节剂，但迄今为止，关于它们在疾病中的功能的信息很少。在造血和内皮细胞区室中缺乏SOCS-3的Socs 3（-/Delta vav）小鼠的产生使我们能够探索内源性SOCS-3在急性炎症性关节炎期间的作用。Socs 3（-/Delta vav）小鼠的关节炎症尤其严重，其特征在于炎症滑膜、骨髓、外周血和脾脏中的中性粒细胞数量增加。这些特征最有可能是由于这些小鼠关节炎期间G-CSF和IL-6的产生增加和对G-CSF和IL-6的反应性增强。在没有SOCS-3的情况下，局部破骨细胞生成和骨破坏也显著增加，巨噬细胞活化也是如此。最后，发现SOCS-3负调节CD 4（+）T淋巴细胞活化，包括多效性细胞因子IL-17的产生。因此，SOCS-3的缺乏在这种疾病模型中具有显著的影响，对细胞反应的影响比SOCS-1缺乏更广泛。这些发现提供了直接的体内证据，即内源性SOCS-3是协调炎性关节疾病的多种细胞类型的关键负调节因子。
RA is an autoimmune disease characterized by sustained imbalance between pro- and antinflammatory immune mechanisms. The SOCS proteins are negative regulators of cytokine signaling, but to date there has been little information on their function in disease. The generation of Socs3(-/Delta vav) mice, which lack SOCS-3 in the hematopoietic and endothelial cell compartment, allowed us to explore the role of endogenous SOCS-3 during acute inflammatory arthritis. Joint inflammation in Socs3(-/Delta vav) mice was particularly severe and was characterized by increased numbers of neutrophils in the inflamed synovium, bone marrow, peripheral blood, and spleen. These features were most likely due to increased production of and enhanced responsiveness to G-CSF and IL-6 during arthritis in these mice. Local osteoclast generation and bone destruction were also dramatically increased in the absence of SOCS-3, as was macrophage activation. Finally, SOCS-3 was found to negatively regulate CD4(+) T lymphocyte activation, including production of the pleiotropic cytokine IL-17. The absence of SOCS-3 therefore had dramatic effects in this disease model, with a broader impact on cellular responses than SOCS-1 deficiency. These findings provide direct in vivo evidence that endogenous SOCS-3 is a critical negative regulator of multiple cell types orchestrating inflammatory joint disease.