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Am. J. Respir. Cell Mol. Biol., Volume 23, Number 3, September, 2000 364-370

Secretory Leukoprotease Inhibitor Augments Hepatocyte Growth Factor Production in Human Lung Fibroblasts

Toshiaki Kikuchi, Tatsuya Abe, Masahiro Yaekashiwa, Yasuyuki Tominaga, Hiroaki Mitsuhashi, Ken Satoh, Toshikazu Nakamura, and Toshihiro Nukiwa

Department of Respiratory Oncology and Molecular Medicine, Division of Cancer Control, Institute of Development, Aging and Cancer, Tohoku University, Sendai; Teijin Institute for Bio-Medical Research, Tokyo; and Division of Biochemistry, Department of Oncology, Biomedical Research Center, Osaka University Medical School, Suita, Japan

Secretory leukoprotease inhibitor (SLPI), an 11.7-kD nonglycosylated serine protease inhibitor, is produced and released into the fluids of mucosal surfaces including human lung. It comprises two domains with homologous amino acid sequences: the N-terminal domain possessing antibacterial activity, and the C-terminal domain with antiprotease activity. Here we report the positive regulation of hepatocyte growth factor (HGF) production in human lung fibroblasts exerted by SLPI or its C-terminal domain under physiologic concentrations (1 to 10 µM). This HGF production by SLPI was unaffected by the addition of interleukin (IL)-1 receptor antagonist. In contrast, human skin fibroblasts exerted no SLPI-stimulated increase in HGF production, despite the fact that IL-1beta increased HGF production with an intensity similar to that of human lung fibroblasts. Both the time-course and dose-response studies in human lung fibroblasts revealed that the induction of HGF messenger RNA (mRNA) and protein occurred in parallel, indicating that the mechanism existed at the steady-state mRNA level. A synthetic elastase inhibitor failed to induce HGF, but alpha 1-antitrypsin also stimulated HGF production in lung fibroblasts. Inactivation of the antiprotease activity of SLPI or its C-terminal domain by an oxidizing agent (N-chlorosuccinimide) abolished their stimulatory effect on HGF production. These findings demonstrate that SLPI exerts a novel HGF induction and functions as an anti-inflammatory and regenerative factor in addition to its role in protease inhibition.




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