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HGF synthesis in human lung fibroblasts is regulated by oncostatin M

¹Institut National de la Santé et de la Recherche Médicale Unité 700, Faculté de médecine Xavier Bichat, Université Paris 7, Paris; and ²Service de Biochimie and ³Service de Pneumologie, Hôpital Bichat-Claude Bernard, Assistance Publique-Hôpitaux de Paris, Paris, France

Submitted 13 April 2005 ; accepted in final form 28 December 2005

Oncostatin M (OSM) is a IL-6 family cytokine locally produced in acute lung injury. Its profibrotic properties suggest a role in lung wound repair. Hepatocyte growth factor (HGF), produced by fibroblasts, is involved in pulmonary epithelial repair. We investigated the role of OSM in HGF synthesis by human lung fibroblasts. We showed that OSM upregulated HGF mRNA in MRC5 cells and in human lung fibroblasts, whereas IL-6 and leukemia inhibitory factor did not. OSM induced HGF secretion to a similar extent as IL-1 in both a time- and dose-dependent manner. HGF was released in its cleaved mature form, and its secretion was completely inhibited in the presence of cycloheximide, indicating a de novo protein synthesis. OSM in combination with prostaglandin E₂, a powerful HGF inductor, led to an additive effect. OSM and indomethacin in combination further increased HGF secretion. This could be explained, at least in part, by a moderate upregulation of specific OSM receptor mRNA expression through cyclooxygenase inhibition.These results demonstrate that OSM-induced HGF synthesis did not involve a PGE₂ pathway. OSM-induced HGF secretion was inhibited by PD-98059 (a specific pharmacological inhibitor of ERK1/2), SB-203580 (a p38 MAPK inhibitor), and SP-600125 (a JNK inhibitor) by 70, 82, and 100%, respectively, whereas basal HGF secretion was only inhibited by SP-600125 by 30%. Our results demonstrate a specific upregulation of HGF synthesis by OSM, most likely through a MAPK pathway, and support the suggestion that OSM may participate in lung repair through HGF production.

oncostatin M receptor; prostaglandin E₂; mitogen-activated protein kinase; lung repair; hepatocyte growth factor

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