title: Secretory leukoprotease inhibitor augments hepatocyte growth factor production in human lung fibroblasts.
abstract: 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 microM). 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.
authors.affiliation: Department of Respiratory Oncology and Molecular Medicine, Division of Cancer Control, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Kikuchi
authors.forename: T
authors.initials: T
authors.lastname: Abe
authors.forename: M
authors.initials: M
authors.lastname: Yaekashiwa
authors.forename: Y
authors.initials: Y
authors.lastname: Tominaga
authors.forename: H
authors.initials: H
authors.lastname: Mitsuhashi
authors.forename: K
authors.initials: K
authors.lastname: Satoh
authors.forename: T
authors.initials: T
authors.lastname: Nakamura
authors.forename: T
authors.initials: T
authors.lastname: Nukiwa
mesh_terms: D001665:Binding Sites / Q000502:physiology; D002478:Cells, Cultured; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D005347:Fibroblasts / Q000166:cytology / Q000201:enzymology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000502:physiology; D017228:Hepatocyte Growth Factor / Q000096:biosynthesis*; D006801:Humans; D007375:Interleukin-1 / Q000378:metabolism; D008168:Lung / Q000166:cytology / Q000201:enzymology*; D010084:Oxidation-Reduction; D017434:Protein Structure, Tertiary; D053491:Proteinase Inhibitory Proteins, Secretory; D011506:Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D053481:Secretory Leukocyte Peptidase Inhibitor; D015842:Serine Proteinase Inhibitors / Q000235:genetics*; D013388:Succinimides / Q000494:pharmacology
chemical_list: D007375:Interleukin-1; D053491:Proteinase Inhibitory Proteins, Secretory; D011506:Proteins; D012333:RNA, Messenger; C506814:SLPI protein, human; D053481:Secretory Leukocyte Peptidase Inhibitor; D015842:Serine Proteinase Inhibitors; D013388:Succinimides; C015752:N-chlorosuccinimide; D017228:Hepatocyte Growth Factor