BACKGROUND: Endoplasmic reticulum stress (ERS) has been studied as critical factor during occurrence and development of ulcerative colitis (UC). However, the role of ERS in inflamed UC remains unclear. AIMS: The purpose of this study was to analyze the role of inositol-requiring kinase 1 (IRE-1), a major regulator of ER, in regulating ERS and cell viability. METHODS: In UC mucosa tissue, IRE-1, BiP, XBP-1s, CHOP caspase-12 and GADD34 mRNA were assayed by qRT-PCR. Then, human normal colon epithelial cell line (NCM-460) and colon fibroblast cell line (CCD-33Co) were cultured, and downregulated or upregulated IRE-1 expression. ERS was induced with 100 ng/mL of Interleukin 6 (IL-6). CCK8 assay was performed to analyze cell proliferation. Flow cytometry analysis was conducted to detect the apoptosis. Western blot assay was used to examine ERS markers. RESULTS: IRE-1, BiP, XBP-1s, caspase-12 and CHOP mRNA were highly expressed in UC mucosa tissue, and the expression of GADD34 mRNA significantly decreased. These results show that ERS-induced unfolded protein response was enhanced in UC mucosa tissue. In cells, silencing the expression of IRE-1 could suppress cell proliferation and promote apoptosis through activating unfolded protein response, while the over-expression of IRE-1 had the opposite effect. IL-6 could induce ERS and cells apoptosis. Furthermore, we demonstrated that shRNA IRE-1 could enhance the inhibition of IL-6 on cells viability. CONCLUSIONS: Inhibition of IRE-1 enhanced unfolded protein response and cells apoptosis and IL-6-induced ERS and suggested that IRE-1 might be a potential target of UC.