The IBD-associated long noncoding RNA IFNG-AS1 regulates the balance between inflammatory and anti-inflammatory cytokine production after T-cell stimulation

Abstract

The inflammatory bowel diseases (IBD) are a complex set of chronic gastrointestinal inflammatory conditions arising from the interplay of genetic and environmental factors. This study focuses on noncoding RNA transcripts as potential mediators of IBD pathophysiology. One particular gene, interferon γ-antisense 1 ( IFNG-AS1), has been consistently observed to be elevated in the intestinal mucosa of patients with actively inflamed IBD versus healthy controls. This study builds on these observations, demonstrating that the second splice variant is specifically altered, and this alteration even stratifies within inflamed patients. With the use of a CRISPR-based overexpression system, IFNG-AS1 was selectively overexpressed directly from its genomic loci in T cells. An unbiased mRNA array on these cells identified a large increase in many inflammatory cytokines and a decrease in anti-inflammatory cytokines after IFNG-AS1 overexpression. Media from T cells overexpressing IFNG-AS1 elicited an inflammatory signaling cascade in primary human peripheral blood mononuclear cells, suggesting the potential functional importance of IFNG-AS1 in IBD pathophysiology. The significance of these results is amplified by studies suggesting that a single-nucleotide polymorphism in IFNG-AS1, rs7134599, was associated with both subtypes of patients with IBD independently of race. NEW & NOTEWORTHY Long noncoding RNAs are an emerging field of inflammatory bowel disease (IBD) research. This study mechanistically analyzes the role of a commonly upregulated gene in IBD and shows IFNG-AS1 as a mediator of an inflammatory signaling cascade.

Emerging Role of Non-Coding RNAs in Regulation of T-Lymphocyte Function

“…Specific over-expression of IFNG-AS1 in T cells has led to significant enhancement of inflammatory cytokines, while attenuation of production of anti-inflammatory cytokines. Media from IFNG-AS1-overexpressing T cells has induced a potent inflammatory response in primary human peripheral blood mononuclear cells (PBMCs) ( 72 ). Lnc-ITSN1-2 is another lncRNA that affect T cells differentiation.…”

Potential impact and mechanism of Long Non-coding RNAs on cancer and associated T cells

“…Studies have shown that lncRNA IFNG-AS1, also known as Tmevpg1, regulates the production of IFN-γ [45]. For example, Carl Robert Rankin et al verified IFNG-AS1 promotes the production of IFN-γ, thus exacerbating inflammatory bowel disease (IBD) [46] and Juan Wang et al found TMEVPG1 enhances the immune response of Th1 cells in patients with Sjogren syndrome [47]. In addition, a large number of other studies have shown that IFNG-AS1 enhances the immune response of Th1 and is associated with autoimmune diseases such as Multiple sclerosis (MS) and Hashimoto's Thyroiditis (HT) [48,49].…”

Which long noncoding RNAs and circular RNAs contribute to inflammatory bowel disease?

“…There is a positive link between IFNG-AS1 over-expression and the crucial inflammatory cytokine IFNG expression in immune cells 99 . Moreover, Rankin et al 100 illustrated that the IFNG-AS1 gene is located beside the inflammatory cytokine IL-22 gene and extensively regulates the proinflammatory cascade. IFNG-AS1 may promote the effects of Th1 cytokines (IFNG, IL-2) and reduce the effects of Th2 cytokines (IL-10, IL-13) through an MLL/ SET1 mechanism 100 .…”

“…Moreover, Rankin et al 100 illustrated that the IFNG-AS1 gene is located beside the inflammatory cytokine IL-22 gene and extensively regulates the proinflammatory cascade. IFNG-AS1 may promote the effects of Th1 cytokines (IFNG, IL-2) and reduce the effects of Th2 cytokines (IL-10, IL-13) through an MLL/ SET1 mechanism 100 . Overall, lncRNA IFNG-AS1 is a potential target for treating patients with colitis.…”