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B Activation and a Reciprocal Suppression of TGF-
Signal Pathway1
* Department of Forensic Medicine, Wakayama Medical University, Wakayama, Japan;
Department of Molecular Preventive Medicine, School of Medicine, University of Tokyo, Tokyo, Japan; and
Division of Molecular Bioregulation, Cancer Research Institute, Kanazawa University, Kanazawa, Japan
Although enhanced expression of IL-1 family proteins, including IL-1
, IL-1
, 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-, 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-
B, a major target of IL-1- and TNF--mediated signal pathway, we examined the activation states of NF-B. Nuclear translocation of NF-B p65 was significantly enhanced and prolonged in IL-1ra-deficient mice, compared to that in WT mice. The cross-talk between NF-B and TGF--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-1, was decreased in IL-1ra-deficient mice. Thus, the absence of IL-1ra may suppress TGF--mediated signaling pathway, which is crucial for collagen deposition and vascular endothelial growth factor-mediated neovascularization in wound healing.
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