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Osteopontin (OPN) is a multifunctional 34-kDa extracellular matrix protein that can influence the inflammatory process. However, the presence of OPN in human sinonasal mucosa and its roles in the inflammatory process of chronic rhinosinusitis (CRS) are not clear. This study investigated the expression of OPN in human sinonasal mucosa, its cytokine-driven expression regulation, and its effect on cytokine production in sinonasal mucosa.Surgical samples were investigated by means of quantitative reverse transcriptase polymerase chain reaction for evaluation of OPN messenger RNA (mRNA) expression, and the presence and location of OPN protein expression were analyzed using immunohistochemistry. Furthermore, nasal explant culture was used to investigate the mutual regulatory interactions between interferon (IFN)-γ, interleukin (IL)-4, IL-5, IL-13, IL-1β, and tumor necrosis factor (TNF)-α and OPN in sinonasal mucosa.Osteopontin expression was significantly upregulated in CRS tissues compared with control tissues. There was a further significant increase of OPN expression in patients with nasal polyps (NPs) and asthma. Immunohistochemistry revealed positive staining of OPN in epithelial cells, submucosal glands, infiltrating cells, and extracellular matrix. Osteopontin mRNA was induced by IFN-γ, IL-1β, and TNF-α, but inhibited by IL-4 and IL-13. On the contrary, OPN induced IFN-γ, IL-4, IL-5, IL-13, IL-1β, and TNF-α production in sinonasal mucosa.The expression of OPN is upregulated in CRS. The mutual regulatory interactions between OPN and inflammatory cytokines suggest that OPN may play an important role in the pathogenesis of CRS.