title: Osteopontin Potentiates Pulmonary Inflammation and Fibrosis by Modulating IL-17/IFN-γ-secreting T-cell Ratios in Bleomycin-treated Mice.
abstract: Lung fibrosis is a life-threatening disease caused by overt or insidious inflammatory responses. However, the mechanism of tissue injury-induced inflammation and subsequent fibrogenesis remains unclear. Recently, we and other groups reported that Th17 responses play a role in amplification of the inflammatory phase in a murine model induced by bleomycin (BLM). Osteopontin (OPN) is a cytokine and extracellular-matrix-associated signaling molecule. However, whether tissue injury causes inflammation and consequent fibrosis through OPN should be determined. In this study, we observed that BLM-induced lung inflammation and subsequent fibrosis was ameliorated in OPN-deficient mice. OPN was expressed ubiquitously in the lung parenchymal and bone-marrow-derived components and OPN from both components contributed to pathogenesis following BLM intratracheal instillation. Th17 differentiation of CD4(+) αβ T cells and IL-17-producing γδ T cells was significantly reduced in OPN-deficient mice compared to WT mice. In addition, Th1 differentiation of CD4(+) αβ T cells and the percentage of IFN-γ-producing γδ T cells increased. T helper cell differentiation in vitro revealed that OPN was preferentially upregulated in CD4(+) T cells under Th17 differentiation conditions. OPN expressed in both parenchymal and bone marrow cell components and contributed to BLM-induced lung inflammation and fibrosis by affecting the ratio of pathogenic IL-17/protective IFN-γ T cells.
authors.affiliation: Laboratory of Immunology and Cancer Biology, Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 110-799, Korea. ; Transplantation Research Institute, Seoul National University College of Medicine, Seoul 110-799, Korea.
authors.forename: Keunhee
authors.initials: K
authors.lastname: Oh
authors.affiliation: Laboratory of Immunology and Cancer Biology, Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 110-799, Korea.
authors.forename: Myung Won
authors.initials: MW
authors.lastname: Seo
authors.affiliation: Department of Internal Medicine, Seoul National University College of Medicine, Seoul 110-799, Korea.
authors.forename: Young Whan
authors.initials: YW
authors.lastname: Kim
authors.affiliation: Laboratory of Immunology and Cancer Biology, Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 110-799, Korea. ; Transplantation Research Institute, Seoul National University College of Medicine, Seoul 110-799, Korea.
authors.forename: Dong-Sup
authors.initials: DS
authors.lastname: Lee
keywords: IL-17; Osteopontin; Pulmonary fibrosis; Th17 differentiation; αβ T cells