Abstract
Background We reported that MMP-9, regulated by various cytokines, could play an important part of vascular remodeling in Kawasaki disease (KD). However, it is still unclear what kind of interaction among cytokines (as cytokine network) regulates MMP-9 expression. Therefore, we focused on hHGF, one of the strongest angiogenetic factors produced by various cells including vascular component cells, and investigated the regulatory mechanisms of MMP-9 under cytokine network centering on hHGF in KD. Subjects 30 KD patients (group KD: M 19, F11; 3m-5y), 10 healthy controls (H: M 5, F 5; 5m-3y) and 10 febrile controls (F: M5, F5; 10m-4y). Methods Plasma MMP-9 and hHGF were measured by ELISA. After treatment with plasma samples or cytokines including hHGF, the levels of mRNA for MMP-9, hHGF and cMET in HUVEC and fibroblasts were detected by RT-PCR (quantitative or not). Results Plasma MMP-9 and hHGF levels markedly increased during all phases in KD (MMP-9; H 31.8 ± 12.1 ng/ml, F 109.9 ± 87.1, KD pre-IVIG 304.5 ± 269.0, post-IVIG 130.5 ± 116.5, 1 m 77.7 ± 73.4 and hHGF; 0.09 ± 0.06 ng/ml, 0.32 ± 0.16, 0.92 ± 0.49, 0.37 ± 0.19 and 0.45 ± 0.69, respectively). There was a significant positive correlation between MMP-9 and hHGF. The assessed levels of mRNA for MMP-9 in HUVEC were significantly higher in KD pre-IVIG phase, and stimulated by hHGF in a dose dependent manner. IL-6 enhanced hHGF expression in fibroblasts. Messenger RNA for cMET was significantly enhanced in HUVEC under co-culture with IL-6 stimulating fibroblasts, and was suppressed by additional using anti-hHGF antibody. Conclusion It was suggested that hHGF, produced by fibroblasts stimulated by other cytokines, could regulate the synthesis of MMP-9 by endothelial cells in KD.
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Sakata, K., Ozawa, SI., Hamaoka, K. et al. Matrix Metalloproteinase-9 (MMP-9) Regulation by Cytokine Network Centering on Human Hepatocyte Growth Factor (hHGF) in Kawasaki Disease. Pediatr Res 53, 169 (2003). https://doi.org/10.1203/00006450-200301000-00096
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DOI: https://doi.org/10.1203/00006450-200301000-00096