MCP‐1‐Induced Protein Promotes Human Pulmonary Fibroblast Migration Induced by SiO2 via MAPKs and PI3K Signaling

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Silicosis is a systemic disease caused by inhalation of silicon dioxide (SiO2). Phagocytosis of SiO2 in the lung causes inflammatory cascade resulting in fibroblast proliferation and migration with subsequent fibrosis. Clinical evidence indicated that activation of alveolar macrophage induced by SiO2 produces a rapid and sustained inflammation characterized by generation of monocyte chemotactic protein 1 (MCP-1), which, in turn, induces fibrosis. Our previous studies suggested that MCP-1-induced protein 1 (MCPIP1, ZC3H12A), downstream of MCP-1, played a critical role in fibroblast proliferation and migration. Here we investigated the mechanism of fibroblast migration induced by SiO2 with emphasis on MCPIP1 Experiments in primary cultured human pulmonary fibroblast (adult) showed: 1). SiO2 induced release of MCPIP1 in a concentration and time dependent manner. 2). Cellular migration was up-regulated in both scratch assay and 3D collagen matrix model in the presence of SiO2 (50µg/cm2). 3). Rapid and transient activation of ERK, p38, JNK and Akt also occurred after SiO2; pharmacologic inhibition of each kinase reduced MCPIP1 expression and blunted the migration induced by SiO2. 4). RNA interference of MCPIP1 prevented the increased migration which occurred after SiO2. These data demonstrated that up-regulation of MCPIP1 was involved in cell migration of pulmonary fibroblast induced by SiO2. Signaling events upstream of MCPIP1 induction included activation of MAP kinases and PI3K. Our study deciphered the link between MCPIP1 and cellar migration induced by SiO2, providing a novel insight into the potential of MCPIP1 in terms of opening up novel therapeutic avenues for silicosis.