Endoplasmic Reticulum Stress Aggravates Inflammatory Bowel Disease by Triggering TLR2 Signaling Pathway

Abstract Background: Endoplasmic reticulum stress (ERS) and Toll-like receptor 2 (TLR2) signaling play an important role in inflammatory bowel disease (IBD); however, the link between TLR2 and ERS in IBD is unclear. This study investigated whether ERS and TLR2 mutually regulate and have a pro-inflammatory role in IBD pathogenesis. Methods: The THP-1 cells were treated with TLR2 agonist (Pam3CSK4), ERS inducer (TG) or inhibitor (TUDCA). The expressions of TLR1-TLR10 were detected by qRT-PCR or Western blot analysis . The expressions of TNF-α, IL-1β, IFN-β and IL-8 were measured by qRT-PCR and ELISA. The IBD mouse model was established by TNBS in the modeling group. TUDCA was used in the treatment group. The degree of colitis was assessed by comparing histological scores and DAI scores in each group.The expressions of Grp78 and TLR2 in intestinal mucosa were detected by immunohistochemistry. Results: The ERS inducer (TG) can increase the expressions of TLR2 and TLR5 after inducing ERS in THP-1 cells, while this effect is inhibited by TUDCA. However, the TLR2 agonist (Pam3CSK4) has no significant effect on the expressions of GRP78 and CHOP proteins. Treatment of THP-1 cells by TG and Pam3CSK4 together can significantly promote the expression of TNF-α, IL-1β and IL-8. In vivo experiments, TUDCA can inhibit intestinal mucosal inflammation and the expressions of Grp78 and TLR2. Compared with normal controls, the protein expressions of GRP78 and TLR2 in the colon mucosa of CD patients were significantly elevated. Conclusions: ERS aggravates inflammatory reaction in IBD by activating the TLR2 signaling pathway, making it a potential therapeutic target for IBD.