Oncostatin M (OSM) may promote type 2 inflammation in chronic rhinosinusitis with nasal polyps (CRSwNP) by inducing thymic stromal lymphopoietin (TSLP).To study the impact of OSM on TSLP synthesis and release from nasal epithelial cells (NEC).OSM receptors (OSMR), IL-4 receptors (IL-4R), and TSLP were evaluated in mucosal tissue and primary NEC from CRSwNP patients by quantitative PCR (qPCR) and immunofluorescence. Air-liquid interface (ALI) cultured NEC were stimulated with cytokines including OSM, and qPCR, enzyme-linked immunosorbent assay (ELISA), western blot and flow cytometry were used to assess expression of OSMR, IL-4R and TSLP.Increased levels of OSMRβ, IL-4Rα, and TSLP were observed in NP tissue and primary epithelial cells from NP of patients with CRSwNP, compared with control tissue or cells from control subjects. The level of expression of OSMRβ in tissue was correlated with levels of both IL-4Rα and TSLP. OSM stimulation of NEC increased expression of OSMRβ and IL-4Rα. Stimulation with IL-4 plus OSM augmented the production of TSLP; the response was suppressed by a STAT6 inhibitor. Stimulation of NEC with IL-4 plus OSM increased the expression of the proprotein convertase subtilisin/kexin3 (PCSK3), an enzyme that truncates and activates TSLP.OSM increases the expression of IL-4Rα and synergizes with IL-4 to induce the synthesis and release of TSLP in NEC. Since the combination of IL-4 and OSM also augmented expression of PCSK3, these results suggest that OSM can induce both synthesis and posttranslational processing/activation of TSLP, promoting type 2 inflammation.Copyright © 2023. Published by Elsevier Inc.