Alpha-defensin enhances expression of HSP47 and collagen-1 in human lung fibroblasts.
Neutrophils and lung fibroblasts are thought to play a role in the pathogenesis of pulmonary fibrosis. We reported previously that heat shock protein 47 (HSP47), a collagen-specific molecular chaperon, and collagen-1 synthesis were involved in pulmonary fibrosis, and that plasma levels of alpha-defensins (HNP; human neutrophil peptide), cationic proteins with antimicrobial and cytotoxic activity in neutrophils, were significantly higher in patients with idiopathic pulmonary fibrosis than in control subjects. Here, we investigated the direct effect of HNP-1 in vitro on the expression of HSP47 and collagen-1 in human lung fibroblasts (NHLF). HNP-1 at 5 microg/ml induced fibroblast proliferation but at concentrations >50 microg/ml, HNP-1 reduced cell viability. Incubation of NHLF with 10 to 25 microg/ml of HNP-1 for 24-h increased the expression of HSP47 and collagen-1 mRNAs (p<0.05). The levels of HSP47 protein also increased significantly at 50 microg/ml, and those of collagen-1 protein increased at 10 to 50 microg/ml of HNP-1 (p<0.05). The mitogen-activated protein kinase (MAPK) signaling pathway in NHLF was activated by HNP-1 stimulation, but inhibitor of MEK (PD98059) did not block HNP-1-induced HSP47 protein production. Our results suggest that alpha-defensin is a fibrogenic mediator that promotes collagen synthesis through the upregulation of HSP47 and collagen-1 in lung fibroblasts and participates in the pathogenesis of neutrophil-induced pulmonary fibrosis.
Yoshioka
Sumako
S
Second Department of Internal Medicine, Nagasaki University School of Medicine, 1-7-1 Sakamoto, Nagasaki, 852-8501 Japan.
Mukae
Hiroshi
H
Ishii
Hiroshi
H
Kakugawa
Tomoyuki
T
Ishimoto
Hiroshi
H
Sakamoto
Noriho
N
Fujii
Takeshi
T
Urata
Yoshie
Y
Kondo
Takahito
T
Kubota
Hiroshi
H
Nagata
Kazuhiro
K
Kohno
Shigeru
S
D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D024042:Collagen Type I / Q000378:metabolism*; D023082:Defensins / Q000494:pharmacology*; D005347:Fibroblasts / Q000187:drug effects* / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects*; D050958:HSP47 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008168:Lung / Q000166:cytology; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D023084:alpha-Defensins / Q000494:pharmacology
D024042:Collagen Type I; D023082:Defensins; D050958:HSP47 Heat-Shock Proteins; D012333:RNA, Messenger; D023084:alpha-Defensins; C406413:human neutrophil peptide 1; D020928:Mitogen-Activated Protein Kinases