Absence of IL-1 receptor antagonist impaired wound healing along with aberrant NF-kappaB activation and a reciprocal suppression of TGF-beta signal pathway.
Absence of IL-1 receptor antagonist impaired wound healing along with aberrant NF-kappaB activation and a reciprocal suppression of TGF-beta signal pathway.
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发表时间：
2006
影响因子：
4.4
通讯作者：
Y. Ishida;T. Kondo;A. Kimura;K. Matsushima;N. Mukaida
中科院分区：
文献类型：
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作者：
Y. Ishida;T. Kondo;A. Kimura;K. Matsushima;N. Mukaida
尽管已经观察到IL-1家族蛋白，包括IL-1 α、IL-1 β和IL-1受体拮抗剂（IL-1 ra）在伤口愈合期间的增强表达，但是这些因子，特别是IL-1 ra的病理生理作用仍然是难以捉摸的。我们探索了IL-1 ra缺陷小鼠的皮肤伤口愈合过程。与野生型（WT）小鼠相比，IL-1 ra缺陷小鼠表现出受损的伤口愈合，如减弱的胶原沉积和延迟的新血管形成所证明的。相比之下，与WT小鼠相比，IL-1 ra缺陷小鼠中的中性粒细胞募集显著放大，IL-1 s，TNF-α和CXC趋化因子MIP-2和KC的表达增加。由于这些促炎细胞因子和CXC趋化因子的转录需要NF-κ B的活化，NF-κ B是IL-1和TNF-α介导的信号通路的主要靶点，因此我们检查了NF-κ B的活化状态。与WT小鼠相比，IL-1 ra缺陷小鼠的NF-κ B p65核转位显著增强和延长。已经基于体外观察提出了NF-κ B和TGF-β介导的信号之间的串扰。事实上，与WT小鼠相比，总的和磷酸化的Smad 2和Smad 3的量减少，而在IL-1 ra缺陷小鼠的皮肤伤口部位中Smad 7的量则相反地增加。此外，在IL-1 ra缺陷小鼠中，TGF-β 1的靶基因血管内皮生长因子的基因表达降低。因此，IL-1 ra的缺乏可能会抑制TGF-β介导的信号通路，这是至关重要的胶原蛋白沉积和血管内皮生长因子介导的新生血管在伤口愈合。
Although enhanced expression of IL-1 family proteins, including IL-1alpha, IL-1beta, and IL-1 receptor antagonist (IL-1ra) during wound healing has been observed, the pathophysiological roles of these factors, particularly IL-1ra, still remain elusive. We explored skin wound-healing processes in IL-1ra-deficient mice. Compared to wild-type (WT) mice, IL-1ra-deficient mice exhibited impaired wound healing, as evidenced by attenuated collagen deposition and delayed neovascularization. In contrast, neutrophil recruitment was significantly exaggerated, with the augmented expression of IL-1s, TNF-alpha, and CXC chemokines, MIP-2 and KC, in IL-1ra-deficient mice compared with WT mice. Because the transcription of these proinflammatory cytokines and CXC chemokines requires the activation of NF-kappaB, a major target of IL-1- and TNF-alpha-mediated signal pathway, we examined the activation states of NF-kappaB. Nuclear translocation of NF-kappaB p65 was significantly enhanced and prolonged in IL-1ra-deficient mice, compared to that in WT mice. The cross-talk between NF-kappaB and TGF-beta-mediated signals has been proposed based on in vitro observations. Indeed, compared to WT mice, the amounts of total and phosphorylated Smad2 and Smad3 were decreased with a reciprocal increase in the amount of Smad7 in skin wound sites of IL-1ra-deficient mice. Moreover, the gene expression of vascular endothelial growth factor, a target gene of TGF-beta1, was decreased in IL-1ra-deficient mice. Thus, the absence of IL-1ra may suppress TGF-beta-mediated signaling pathway, which is crucial for collagen deposition and vascular endothelial growth factor-mediated neovascularization in wound healing.