Abstract
Background: This study aimed to investigate long-non-coding RNA (lncRNA) expression profiles and the correlation of lnc-ITSN1-2 expression with disease risk, activity and inflammation, and its influence on CD4+ T cell activation, proliferation, and differentiation of inflammatory bowel disease (IBD).Methods: LncRNA expression profiles were detected in intestinal mucosa samples from six IBD patients and six healthy controls (HCs). Intestinal mucosa and PBMC lnc-ITSN1-2, IL-23R, and inflammatory cytokines were measured in 120 IBD patients [60 Crohn's disease (CD) and 60 ulcerative colitis (UC)] and 30 HCs. Effect of lnc-ITSN1-2 on IBD CD4+ T cell activation, proliferation, and differentiation was determined and its regulatory interaction with miR-125a and IL-23R was detected.Results: Three-hundred-and-nine upregulated and 310 downregulated lncRNAs were identified in IBD patients by RNA-Sequencing, which were enriched in regulating immune and inflammation related pathways. Large-sample qPCR validation disclosed that both intestinal mucosa and PBMC lnc-ITSN1-2 expressions were increased in IBD patients compared to HCs, and presented with good predictive values for IBD risk, especially for active disease conditions, and they positively correlated with disease activity, inflammation cytokines, and IL-23R in IBD patients. Lnc-ITSN1-2 was decreased after infliximab treatment in active-CD patients. Furthermore, lnc-ITSN1-2 promoted IBD CD4+ T cell activation and proliferation, and stimulated Th1/Th17 cell differentiation. Multiple rescue experiments disclosed that lnc-ITSN1-2 functioned in IBD CD4+ T cells via targeting miR-125a, then positively regulating IL-23R. Luciferase Reporter assay observed that lnc-ITSN1-2 bound miR-125a, and miR-125a bound IL-23R.Conclusion: Lnc-ITSN1-2 correlates with increased disease risk, activity, and inflammatory cytokines of IBD, and promotes IBD CD4+ T cell activation, proliferation, and Th1/Th17 cell differentiation by serving as a competing endogenous RNA for IL-23R via sponging miR-125a.
Highlights
Inflammatory bowel disease (IBD), mainly consisting of Crohn’s disease (CD) and ulcerative colitis (UC), is a severe gastrointestinal disorder that affects people of all ages worldwide with a continuously increasing incidence [1, 2]
The top 10 upregulated and the top 10 downregulated differentially expressed lncRNAs (DELs) in IBD patients compared to healthy controls (HCs) were selected by rank of absolute value of Log2FC which are listed in Table 1, and the regulatory network of these 20 DELs was analyzed and is shown in Supplementary Figure 2
For detection of IBD CD4+ T cell activation, we found that CD25+ cell percentage (Figures 9A,B) and CD69+ cell percentage (Figures 10A,B) were both elevated in the LV-lnc-ITSN1-2 group while reduced in the LV-anti-lnc-ITSN12 group compared to the LV-scramble group
Summary
Inflammatory bowel disease (IBD), mainly consisting of Crohn’s disease (CD) and ulcerative colitis (UC), is a severe gastrointestinal disorder that affects people of all ages worldwide with a continuously increasing incidence [1, 2]. Despite the fact that the exact pathogenesis of IBD is still largely unknown, it involves a complex interaction between genetics, environmental factors, and immune responses, among which genetic studies have recently made the most rapid progress [1,2,3]. The functions of most lncRNAs in IBD development and progression are still vastly unknown, and is in great need of further investigation. This study aimed to investigate long-non-coding RNA (lncRNA) expression profiles and the correlation of lnc-ITSN1-2 expression with disease risk, activity and inflammation, and its influence on CD4+ T cell activation, proliferation, and differentiation of inflammatory bowel disease (IBD)
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