Abstract
Background: The long non-coding RNA (lncRNA) growth arrest–specific transcript 5 (GAS5) seems to be involved in the regulation of mediators of tissue injury, in particular matrix metalloproteinases (MMPs), implicated in the pathogenesis of inflammatory bowel disease (IBD). We investigated the role of GAS5 in regulating MMP2 and MMP9 expression in pediatric patients with IBD and in vitro. Methods: In total, 25 IBD patients were enrolled: For each patient paired inflamed and non-inflamed biopsies were collected. RNA was extracted and GAS5, MMP2, and MMP9 were quantified by TaqMan assay. The expression of GAS5 and MMPs was also determined in the human monocytic THP1 cells differentiated into macrophages and stimulated with lipopolysaccharide (LPS). The function of GAS5 was assessed by overexpressing the lncRNA and evaluating the MMPs levels. Results: Real-time PCR results demonstrated a downregulation of GAS5 and an upregulation of both MMPs in inflamed tissues. In vitro data confirmed the trend observed in patients for the three genes: The stimulation with LPS promoted a downregulation of GAS5 while an increase of MMPs was observed. Overexpression experiments showed that higher levels of GAS5 lead to a decrease of both enzymes. Conclusion: These results provide new information about the role of GAS5 in IBD: The lncRNA could mediate tissue damage by modulating the expression of MMPs.
Highlights
Inflammatory bowel disease (IBD) includes two different pathologies, Crohn’s disease (CD) and ulcerative colitis (UC), that, different in their pathogenesis, show common clinical characteristics such as chronic inflammation at different levels of the gastrointestinal tract and a dysregulated excessive immune response [1]
Our research focused on the potential role of growth arrest–specific transcript 5 (GAS5) in regulating the transcription of MMP2 and MMP9, starting from their evaluation in inflamed and non-inflamed colonic tissues of pediatric patients with inflammatory bowel disease (IBD)
Considering that activated monocytes and macrophages are the major contributors of MMP9 and MMP2 in inflammatory diseases [17,18], an in vitro study on these cellular models was done to investigate the association between GAS5 and the two matrix metalloproteinases (MMPs)’ expression
Summary
Inflammatory bowel disease (IBD) includes two different pathologies, Crohn’s disease (CD) and ulcerative colitis (UC), that, different in their pathogenesis, show common clinical characteristics such as chronic inflammation at different levels of the gastrointestinal tract and a dysregulated excessive immune response [1] Both CD and UC are characterized by chronic changes in the intestinal tissues, consisting of an intense infiltration of lymphocytes and plasma cells and deep remodeling of the connective tissue, leading to increased turnover of extracellular matrix (ECM) components [2]. Long non-coding RNAs (lncRNAs) have emerged as important gene expression regulatory elements and recent data have implicated the deregulated expression of certain lncRNA networks in the pathogenesis of autoimmune and inflammatory diseases, such as IBD [9,10,11] In this context, one of the most studied lncRNAs is growth arrest–specific transcript 5 (GAS5). Considering that activated monocytes and macrophages are the major contributors of MMP9 and MMP2 in inflammatory diseases [17,18], an in vitro study on these cellular models was done to investigate the association between GAS5 and the two MMPs’ expression
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