Absence of IL-1 receptor antagonist impaired wound healing along with aberrant NF-κB activation and a reciprocal suppression of TGF-β signal pathway
Absence of IL-1 receptor antagonist impaired wound healing along with aberrant NF-κB activation and a reciprocal suppression of TGF-β signal pathway
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DOI：
10.4049/jimmunol.176.9.5598
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发表时间：
2006-05-01
影响因子：
4.4
通讯作者：
Mukaida, Naofumi
中科院分区：
文献类型：
--
作者：
Ishida, Yuko;Kondo, Toshikazu;Mukaida, Naofumi
尽管IL-1家族蛋白，包括IL-1α、IL-1β和IL-1受体拮抗剂(IL-1ra)在伤口愈合过程中的表达增强已被观察到，但这些因子，特别是IL-1ra的病理生理作用仍不清楚。我们探索了IL-1ra缺陷小鼠的皮肤伤口愈合过程。与野生型(WT)小鼠相比，IL-1ra缺乏的小鼠伤口愈合受损，表现为胶原沉积减少和新生血管延迟。相反，与WT小鼠相比，IL-1Ra缺陷小鼠的中性粒细胞募集显著增加，IL-1s、TNF-α和CXC趋化因子MIP-2和KC的表达增强。由于这些致炎细胞因子和CXC趋化因子的转录需要IL-1和TNF-α介导的信号通路的主要靶点--核因子-kappaB的激活，我们检测了核因子-kappa B的激活状态，与IL-1ra缺陷小鼠相比，核转录因子-kappa B p65的核转位显著增强和延长。在体外观察的基础上，已经提出了核因子-KB和转化生长因子-β介导的信号之间的相互作用。事实上，与WT小鼠相比，IL-1ra缺乏的小鼠皮肤伤口处Smad2和Smad3的总量和磷酸化的Smad2和Smad3的数量减少，而Smad7的数量相反增加。此外，在IL-1ra缺陷小鼠中，转化生长因子-β1的靶基因血管内皮生长因子的基因表达降低。因此，IL-1ra的缺失可能抑制了转化生长因子-β介导的信号通路，而转化生长因子-β介导的信号通路在创面愈合过程中对胶原沉积和血管内皮生长因子介导的新生血管形成至关重要。
Although enhanced expression of IL-1 family proteins, including IL-1 alpha, IL-1 beta, 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-kappa B, a major target of IL-1- and TNF-alpha-mediated signal pathway, we examined the activation states of NF-kappa B. Nuclear translocation of NF-kappa B p65 was significantly enhanced and prolonged in IL-1ra-deficient mice, compared to that in WT mice. The cross-talk between NF-KB 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-beta 1, 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.