Am. J. Respir. Cell Mol. Biol., Volume 26, Number 2, February, 2002 231-238

Interferon- Inhibits Hepatocyte Growth Factor-Stimulated Cell Proliferation of Human Bronchial Epithelial Cells
Upregulation of p27^kip1 Cyclin-Dependent Kinase Inhibitor

Kazutaka Takami, Noriko Takuwa, Hitoshi Okazaki, Masato Kobayashi, Takayuki Ohtoshi, Shin Kawasaki, Makoto Dohi, Kazuhiko Yamamoto, Toshikazu Nakamura, Mitsuru Tanaka, Kazuhiko Nakahara, Yoh Takuwa, and Hajime Takizawa

Departments of Respiratory Medicine, Laboratory Medicine, Allergology, and Rheumatology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan; Department of Physiology, Kanazawa University School of Medicine, Kanazawa, Japan; Third Department of Internal Medicine and WHO Collaborating Center, Tokyo Medical College, Tokyo, Japan; and Department of Oncology, Biomedical Research Center, Osaka University Medical School, Osaka, Japan

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- (IFN-). 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- 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- 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- does not interfere with the effects of HGF on either ERK activation or cyclin D1 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- in the repair processes of injured human bronchial epithelial cells.

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