Abstract
Acute pancreatitis (AP) is a serious condition associated with intestinal barrier disruption or inflammation of the pancreatic tissue. Specific microRNAs are involved in the pathogenesis of AP, during which IL-17-producing CD4+ T helper (Th17) cells accumulate in the pancreas. In this study, significantly increased levels of miR-155 were detected in clinical samples from patients with AP, and overexpression of miR-155 correlated with severe AP (SAP). To identify the effect of miR-155 on T cell differentiation, we isolated CD4+ T lymphocytes and in vitro experiments showed that inhibition of miR-155 significantly reversed the stress-induced increase in the Th17/Treg ratio. The results also showed that miR-155 increased the Th17-mediated inflammatory response by targeting SOCS1. The interaction between miR-155 and the 3′-UTR of SOCS1 was confirmed by a dual luciferase reporter assay and RT-PCR. Experimental AP of varying severity was induced in BALB/c mice by caerulein hyperstimulation and miR-155 expression was found to increase with disease progression. Inhibition of miR-155 expression significantly improved the pathology of the pancreas. We also observed downregulation of expression of inflammatory factors, IL-17, SOCS1 and phosphorylated STAT1 after miR-155 inhibition. In summary, miR-155 regulates the Th17/Treg ratio by targeting SOCS1, most probably via direct binding to its 3′-UTR region, indicating that this microRNA may be a potential biomarker and/or therapeutic target for AP.
Highlights
Acute pancreatitis (AP) is a condition characterized by sudden inflammation of the pancreas resulting from abnormal activation of digestive enzyme precursors within the pancreas, the most notable of which is trypsinogen
To determine whether miR-155 expression levels differed with disease severity, quantitative RT-PCR analyses of miR-155 expression in the serum of patients diagnosed with AP were performed
The relative SOCS1 expression decreased with increased disease severity, with the severe AP (SAP) group of patients displaying the lowest levels of SOCS1 expression (P < 0.001 vs. AP group, P < 0.001 vs. MAP group)
Summary
Acute pancreatitis (AP) is a condition characterized by sudden inflammation of the pancreas resulting from abnormal activation of digestive enzyme precursors (zymogens) within the pancreas, the most notable of which is trypsinogen. This dysregulation of digestive enzymes leads to autodigestion of the pancreas, inflammation, edema, vascular injury, and in some cases apoptotic or necrotic cell death. The severity of the disease course is determined by whether the predominant response to cellular injury is inflammation and apoptotic cell death (leading to mild, self-limiting, AP, in approximately 80% of cases) or necrotic cell death (leading to severe AP, or SAP, in approximately 20% of cases) (Bhatia, 2004). Patients suffer endotoxemia as a result of apical junction complex damage and intestinal barrier dysfunction (Ammori et al, 1999, Ammori, 2003; Rahman et al, 2003; Capurso et al, 2012) and in severe cases multiple organ failure and death, with a reported mortality rate of 30% (Juvonen et al, 2000; Clark and Coopersmith, 2007; Wu and Banks, 2013)
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