© 2002 American Thoracic Society A Two-way Interaction between Hepatocyte Growth Factor and Interleukin-6 in Tissue Invasion of Lung Cancer Cell LinePulmonary Section, Department of Allergy and Rheumatology, Graduate School of Medicine, University of Tokyo, Tokyo; and Division of Molecular Regenerative Medicine, Department of Regenerative Medicine, Course of Advanced Medicine, Osaka University Graduate School of Medicine, Osaka, Japan Address correspondence to: Makoto Dohi, M.D., Ph.D., Pulmonary Section, Department of Allergy and Rheumatology, Graduate School of Medicine, University of Tokyo, 7-3-1, Hongoh, Bunkyo-ku, Tokyo 113-8655, Japan. E-mail: DOHI-PHY{at}h.u-tokyo.ac.jp Although both hepatocyte growth factor (HGF) and interleukin (IL)-6 play important roles in invasion of cancer cells, interaction between these two critical factors has not been well elucidated. In the present study we demonstrated a two-way interaction between HGF and IL-6 in in vitro invasion of a lung cancer cell line. A549 lung adenocarcinoma cells were stimulated with IL-6, and this treatment induced an upregulation of c-Met/HGF receptor mRNA expression in the cells. In addition, IL-6 enhanced the HGF-induced in vitro cell invasion. This effect was abolished by pretreatment of the cells with either anti–IL-6 neutralizing antibody or with anti–c-Met/HGF receptor blocking antibody. We also found that HGF upregulated the expression of IL-6 receptor mRNA in the same cell line, and that this upregulation enhanced the IL-6–induced cell invasion. Finally, costimulation with HGF and IL-6 showed an additive effect on invasion, and this effect was mediated by production of matrix metalloproteinase (MMP)-2 and MMP-9. These results suggest that HGF and IL-6 upregulate each other's receptors, and thus would cooperatively enhance tissue invasion. They also suggest an "autocrine circuit" among cytokines and growth factors in certain cancer cells which functions to accelerate their biologic activities such as metastatic property.
Abbreviations: fetal calf serum, FCS • glycerylaldehyde-3-phosphate dehydrogenase, GAPDH • hepatocyte growth factor, HGF • interleukin, IL • matrix metalloproteinase, MMP • phosphate-buffered saline, PBS • reverse transcriptase-polymerase chain reaction, RT-PCR • tumor necrosis factor- This article has been cited by other articles:
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