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The Pro-Fibrotic Factor IGFBP-5 Induces Lung Fibroblast and Mononuclear Cell Migration

¹ Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, and ² Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania

Correspondence and requests for reprints should be addressed to Carol A. Feghali-Bostwick, Ph.D., Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Pittsburgh School of Medicine, NW 628 MUH, 3459 Fifth Avenue, Pittsburgh, PA 15213. E-mail: feghalica{at}upmc.edu

We have previously shown that insulin-like growth factor–binding protein-5 (IGFBP-5) is overexpressed in fibrotic lung tissues and that it induces production of extracellular matrix components such as collagen and fibronectin both in vitro and in vivo. We recently observed mononuclear cell infiltration in lung tissues of mice expressing IGFBP-5. We therefore examined the role of IGFBP-5 on the migration of immune cells. Migration assays demonstrated that IGFBP-5 induced migration of peripheral blood mononuclear cells (PBMCs) in a dose-dependent manner. Preferential migration of monocytes/macrophages, natural killer cells, and T cells was observed. Moreover, the CD4/CD8 ratio of migrating cells was significantly higher in vitro and in vivo in response to IGFBP-5. IGFBP-5 resulted in preferential migration of activated CD4⁺ T cells and monocytes. Interestingly, IGFBP-5 also induced migration of primary human lung fibroblasts. Exogenous administration of IGFBP-5 induced activation of mitogen-activated protein kinase (MAPK) signaling cascade but not PI3K in PBMCs. IGFBP-5–induced migration was blocked by the MEK1/2 inhibitor U0126, suggesting that IGFBP-5–induced migration occurs via MAPK activation. Furthermore, monocytes treated with recombinant IGFBP-5 expressed the mesenchymal markers –smooth muscle actin and fibronectin in vitro and in vivo, suggesting that IGFBP-5 can induce the transformation of monocytes into mesenchymal cells. Collectively, our results suggest that IGFBP-5 induces cell migration via MAPK-dependent and IGF-I–independent mechanisms.

Key Words: IGFBP-5 • mononuclear cells • migration • MAPK • fibrosis

CLINICAL RELEVANCE Insulin-like growth factor–binding protein-5 (IGFBP-5) is a novel fibrotic factor. Very little is known about the mechanism by which IGFBP-5 exerts its effect. This research identifies a chemoattractant activity of IGFBP-5 for immune cells and describes the mechanism mediating it. Thus, these findings provide insights into the pathogenic mechanisms mediating pulmonary fibrosis.