Abstract
Intestinal barrier function defects and dysregulation of intestinal immune responses are two key contributory factors in the pathogenesis of ulcerative colitis (UC). Phenazine biosynthesis-like domain-containing protein (PBLD) was recently identified as a tumor suppressor in gastric cancer, hepatocellular carcinoma, and breast cancer; however, its role in UC remains unclear. Therefore, we analyzed colonic tissue samples from patients with UC and constructed specific intestinal epithelial PBLD-deficient (PBLDIEC−/−) mice to investigate the role of this protein in UC pathogenesis. We found that epithelial PBLD was decreased in patients with UC and was correlated with levels of tight junction (TJ) and inflammatory proteins. PBLDIEC−/− mice were more susceptible to dextran sulfate sodium (DSS)- and 2,4,6-trinitrobenzene sulfonic acid-induced colitis compared with wild-type (WT) mice. In DSS-induced colitis, PBLDIEC−/− mice had impaired intestinal barrier function and greater immune cell infiltration in colonic tissue than WT mice. Furthermore, TJ proteins were markedly reduced in PBLDIEC−/− mice compared with WT mice with colitis. Nuclear factor (NF)-κB activation was markedly elevated and resulted in higher expression levels of downstream effectors (C–C motif chemokine ligand 20, interleukin [IL]-1β, IL-6, and tumor necrosis factor [TNF]-α) in colonic epithelial cells isolated from PBLDIEC−/− mice than WT mice with colitis. PBLD overexpression in intestinal epithelial cells (IECs) consistently inhibited TNF-α/interferon-γ-induced intestinal barrier disruption and TNF-α-induced inflammatory responses via the suppression of NF-κB. In addition, IKK inhibition (IKK-16) rescued excessive inflammatory responses induced by TNF-α in PBLD knockdown FHC cells. Co-immunoprecipitation assays showed that PBLD may interact with IKKα and IKKβ, thus inhibiting NF-κB signaling, decreasing inflammatory mediator production, attenuating colonic inflammation, and improving intestinal barrier function. Modulating PBLD expression may provide a novel approach for treatment in patients with UC.
Highlights
Ulcerative colitis (UC) is a nonspecific inflammatory bowel disease (IBD) of unknown cause, characterized by periods of relapse and remission and gastrointestinal symptoms, including bloody stool, diarrhea, and abdominal pain[1]
PBLD expression is decreased in patients with UC We compared PBLD expression of paired inflamed and non-inflamed colonic tissue samples taken from people with UC, and found that PBLD mRNA and protein levels were significantly decreased in inflamed colonic tissue samples compared with non-inflamed samples (Fig. 1a, b)
The tight junction (TJ) plays important role in the pathogenesis of UC; we evaluated the expression of TJ proteins, and found that zonula occludens (ZO)-1 and occludin levels were reduced in inflamed tissue samples compared with non-inflamed samples (Fig. 1a, h, i), which was consistent with previously published work[31]
Summary
Ulcerative colitis (UC) is a nonspecific inflammatory bowel disease (IBD) of unknown cause, characterized by periods of relapse and remission and gastrointestinal symptoms, including bloody stool, diarrhea, and abdominal pain[1]. Intestinal barrier dysfunction in UC includes decreased epithelial cell TJ resistance, increased intestinal permeability, and increased microbial exposure to the mucosal immune system, leading to uncontrolled inflammation[10] Apart from their role as a barrier, IECs secrete cytokines and chemokines (TNF-α, interleukin [IL]-1β, IL-8, and C–C motif chemokine ligand [CCL]-20) that mediate the interaction between the gut microbiome and mucosal immune system in response to pro-inflammatory cytokine stimuli or microbial invasion[6,11,12]. The secretion of these factors is primarily regulated by the nuclear factor (NF)-κB signaling pathway[13,14]. Previous research demonstrates the essential role of IECs in intestinal homeostasis; identifying the molecules that regulate IEC functions may shed new light on the pathogenesis of UC
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