Interferon-γ inhibits hepatocyte growth factor-stimulated cell proliferation of human bronchial epithelial cells upregulation of p27kip1 cyclin-dependent kinase inhibitor

被引:22
|
作者
Takami, K
Takuwa, N
Okazaki, H
Kobayashi, M
Ohtoshi, T
Kawasaki, S
Dohi, M
Yamamoto, K
Nakamura, T
Tanaka, M
Nakahara, K
Takuwa, Y
Takizawa, H
机构
[1] Univ Tokyo, Grad Sch Med, Dept Lab Med, Bunkyo Ku, Tokyo 1138655, Japan
[2] Univ Tokyo, Grad Sch Med, Dept Resp Med, Bunkyo Ku, Tokyo 1138655, Japan
[3] Univ Tokyo, Grad Sch Med, Dept Allergol, Bunkyo Ku, Tokyo 1138655, Japan
[4] Univ Tokyo, Grad Sch Med, Dept Rheumatol, Bunkyo Ku, Tokyo 1138655, Japan
[5] Kanazawa Univ, Sch Med, Dept Physiol, Kanazawa, Ishikawa 920, Japan
[6] Tokyo Med Coll, Dept Internal Med 3, Tokyo 160, Japan
[7] Tokyo Med Coll, WHO Collaborating Ctr, Tokyo 160, Japan
[8] Osaka Univ, Sch Med, Dept Oncol, Biomed Res Ctr, Osaka, Japan
关键词
D O I
10.1165/ajrcmb.26.2.4643
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Proliferation of bronchial epithelial cells is an important biologic process in a variety of physiologic and pathologic conditions. In this study, we demonstrate that hepatocyte growth factor (HGF) stimulates proliferation of human bronchial epithelial cells obtained from healthy volunteers. The mitogenic effect of HGF is dependent on costimulation with serum and is completely abrogated by interferon-gamma (IFN-gamma). In the absence of serum, HGF is capable of inducing activation of extracellular signal-regulated kinases (ERK)1 and ERK2, but fails to stimulate proliferation by itself. These effects of HGF and IFN-gamma were reproduced faithfully in BEAS-2B cells, which are an immortalized cell line derived from human bronchial epithelial cells. Further, we investigated the molecular mechanisms underlying the effects of HGF and IFN-gamma in BEAS-2B cells and found that the MEK1 inhibitor PD98059, but not the p38 M-associated protein kinase inhibitor SB203580, abrogates HGF-induced ERK activation and proliferation in response to HGF and serum. In addition, LY294002, which is the specific inhibitor of phosphatidyl inositol 3-kinase, partially inhibited HGF- and serum-stimulated proliferation. We also found that HGF by itself is capable of inducing a G1 cyclin, cyclin D1, but fails to downregulate p27(kip1) cyclin-dependent kinase (CDK) inhibitor, which is a requisite for G1 to S phase cell cycle progression. IFN-gamma does not interfere with the effects of HGF on either ERK activation or cyclin 131 induction; however, it prevents the downregulation of p27(kip1) CDK inhibitor that takes place in response to a combination of HGF and serum. These results indicate that the MEK-ERK signaling pathway is necessary but not sufficient for human bronchial epithelial cell proliferation, and implicate the significance of HGF and IFN-gamma in the repair processes of injured human bronchial epithelial cells.
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收藏
页码:231 / 238
页数:8
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