Absence of IL-1 receptor antagonist impaired wound healing along with aberrant NF-kappaB activation and a reciprocal suppression of TGF-beta signal pathway.
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.
Ishida
Yuko
Y
Department of Forensic Medicine, Wakayama Medical University, 811-1 Kimidera, Wakayama 641-8509, Japan.
Kondo
Toshikazu
T
Kimura
Akihiko
A
Matsushima
Kouji
K
Mukaida
Naofumi
N
D000818:Animals; D019743:Chemokines, CXC / Q000235:genetics; D003094:Collagen / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1 / Q000235:genetics; D007962:Leukocytes; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism*; D012795:Sialoglycoproteins / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D012867:Skin / Q000098:blood supply / Q000293:injuries / Q000378:metabolism / Q000473:pathology; D051785:Smad Proteins / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics; D014945:Wound Healing / Q000235:genetics
D019743:Chemokines, CXC; C507764:Il1rn protein, mouse; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; D016328:NF-kappa B; D012795:Sialoglycoproteins; D051785:Smad Proteins; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; D042461:Vascular Endothelial Growth Factor A; D003094:Collagen