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Oncostatin M (OSM), an inflammatory cytokine of the interleukin-6 (IL-6) superfamily, plays a key role in various biological processes such as modulation of extracellular matrix (ECM), cell proliferation, cell survival, and induction of inflammation. It has been reported that OSM was increased in asthma and pulmonary fibrosis, and thus OSM may play a role in airway remodeling and the development of lung parenchymal fibrosis. Recruitment of lung fibroblasts to the sites of airway injury and subsequent differentiation into myofibroblasts is believed to contribute to excess ECM deposition. In the current study, we assessed the ability of OSM to modulate fibroblast collagen gel contraction, migration toward fibronectin, and expression of a-smooth muscle actin (a-SMA). We demonstrated that OSM augmentsgel contraction, chemotaxis, and a-SMA expression. OSM-augmented fibroblast chemotaxis was mediated by the signal transducer and activator of transcription (STAT3) and p38 mitogenactivatedprotein kinase, while augmentation on gel contraction and a-SMA expression was mediated by STAT3. Neither transforming growth factor-b1 nor PGE2 was involved in mediating OSM effect on the cells.TheTh2 cytokinesIL-4 and IL-13,whichalso are believed to play an important role in promoting lung fibrosis and airway remodeling, actthroughSTAT3,and wedemonstratedthe potential for additive effects of OSM with IL-4 and IL-13. The present study supports the concept that OSM may contribute to tissue remodeling, which may be additive with IL-4 or IL-13. Blockade of OSM or OSM-mediated STAT3 signaling could be a therapeutic target to regulate lung fibrotic mechanisms.
Keywords: chemotaxis; contractility; asthma; fibrosis
Fibroblasts are large, stellate cells that are present in interstitial tissue. They play an important role in wound healing and the development of fibrosis. The activation of fibroblasts into myofibroblasts is believed to contribute to the subepithelial fibrosis present in patients with severely asthma (1). Myofibroblasts secrete proinflammatory cytokines and growth factors as well as extracellular matrix (ECM) proteins, such as collagens, fibronectin, laminin, and elastin. The increased deposition of ECM that characterizes airway remodeling in patients with asthma and lung parenchymal fibrosis in interstitial pulmonary fibrosis is likely to result directly from excessive functions of myofibroblasts (2-4). In this regard, myofibroblasts highly express contractile stress fibers, a-smooth muscle actin (a-SMA), and fibronectin. Oncostatin M (OSM) is a pleiotropic cytokine in the IL-6 superfamily, which is characterized by its use of the common receptor...