Inhibition of miR-378a-3p by Inflammation Enhances IL-33 Levels: A Novel Mechanism of Alarmin Modulation in Ulcerative Colitis.

Published on Nov 20, 2019in Frontiers in Immunology5.085
· DOI :10.3389/FIMMU.2019.02449
Karen Dubois-Camacho6
Estimated H-index: 6
(University of Chile),
David Díaz-Jiménez9
Estimated H-index: 9
(University of Chile)
+ 14 AuthorsMarcela A. Hermoso26
Estimated H-index: 26
(University of Chile)
Sources
Abstract
Ulcerative colitis (UC) is an inflammatory bowel disease (IBD) characterized by mucosa damage associated to an uncontrolled inflammatory response. This immunological impairment leads to altered inflammatory mediators such as IL-33, which is shown to increase in the mucosa of active UC (aUC) patients. MicroRNAs present a distorted feature in inflamed colonic mucosa and are potential IL-33 regulating candidates in UC. Therefore, we studied the microRNA and mRNA profiles in inflamed colonic samples of UC patients, evaluating the effect of a microRNA (selected by in silico analysis and its expression in UC patients), on IL-33 under inflammatory conditions. We found that inflamed mucosa (n=8) showed increased expression of 40 microRNAs and 2120 mRNAs, while 49 microRNAs and 1734 mRNAs were decreased, as determined by microarrays. In particular, IL-33 mRNA showed a 3.8-fold increase and 8 members of a microRNA family (miR-378), which targets IL-33 mRNA in the 3’UTR, were decreased (-3.9 to -3.0 times). We selected three members of the miR-378 family (miR-378a-3p, miR-422a, miR-378c) according to background information and interaction energy analysis, for further correlation analyses with IL-33 expression through RT-qPCR and ELISA respectively. We determined that aUC (n=24) showed high IL-33 levels, and decreased expression of miR-378a-3p and miR-422a compared to inactive UC (n=10) and controls (n=6). While miR-378c do not show a significant difference, miR-378a-3p and miR-422a were inversely correlated with IL-33 expression. To evaluate the possible effect of TNF-alfa on the studied microRNAs, aUC patients with anti-TNF therapy were compared to aUC receiving other treatments. The levels of miR-378a-3p and miR-378c were higher in aUC patients with anti-TNF. In base to these findings we selected miR-378a-3p to exploring the molecular mechanism involved by in vitro assays, showing that over-expression of miR-378a-3p decreased the levels of an IL-33 target sequence β-gal-reporter gene in HEK293 cells. Stable miR-378a-3p over-expression/inhibition inversely modulated IL-33 content and altered viability of HT-29 cells. Additionally, in an inflammatory context, TNF-alfa decreased miR-378a-3p levels in HT-29 cells enhancing IL-33 expression. Together, our results propose a regulatory mechanism of IL-33 expression exerted by miR-378a-3p in an inflammatory environment, contributing to the understanding of UC pathogenesis.
📖 Papers frequently viewed together
201619.82Gut
12 Authors (Chong He, ..., Zhanju Liu)
75 Citations
2020
8 Authors (Chengrong Li, ..., Xiao-jie Gao)
39 Citations
References71
Newest
#1Çiğdem Güngörmez (Harran University)H-Index: 1
#2Hatice Gumushan Aktas (Harran University)H-Index: 3
Last. Ersin Borazan (University of Gaziantep)H-Index: 9
view all 4 authors...
The aim of this study was to determine oncogenic and tumor-suppressing miRNA profiles associated with the development and progression of cancer using tumor tissues from patients with colorectal cancer (stage II) that did not show nodal spread or advanced metastasis to identify potential biomarkers. A microarray system (GeneChip miRNA 4.0 Array chip, Affymetrix) was used to determine the microRNA profiles of five patients with stage II colon cancer based on normal and colon tumor tissues. Of 32 i...
21 CitationsSource
#1Fernando Alvarez (McGill University)H-Index: 7
#2Roman Istomine (McGill University)H-Index: 7
Last. Ciriaco A. Piccirillo (McGill University)H-Index: 55
view all 8 authors...
CD4+Foxp3+ regulatory T (TREG) cells are critical mediators of peripheral tolerance and modulators of immune responses. Functional adaptation of TREG cells, through acquisition of secondary transcription factors is critical for their effector differentiation towards local inflammatory stimuli including infections. The drivers and consequences of this adaptation of TREG cell function remain largely unknown. Using an unbiased screen, we identified receptors of the IL-1 family controlling the adapt...
23 CitationsSource
#1Gebert Lfr (Scripps Research Institute)H-Index: 1
#2Ian J. MacRae (Scripps Research Institute)H-Index: 30
Since their serendipitous discovery in nematodes, microRNAs (miRNAs) have emerged as key regulators of biological processes in animals. These small RNAs form complex networks that regulate cell differentiation, development and homeostasis. Deregulation of miRNA function is associated with an increasing number of human diseases, particularly cancer. Recent discoveries have expanded our understanding of the control of miRNA function. Here, we review the mechanisms that modulate miRNA activity, sta...
744 CitationsSource
#1Junfeng Zhu (Liaoning University)H-Index: 8
#2Ying Xu (Liaoning University)H-Index: 3
Last. Hongsheng Liu (Liaoning University)H-Index: 18
view all 12 authors...
Background. Previously, we have reported that IL-33 functioned as a protective modulator in dextran sulfate sodium- (DSS-) induced chronic colitis by suppressing Th17 cell response in colon lamina propria and IL-33 induced both regulatory B cells (Bregs) and regulatory T cells (Tregs) in mesenteric lymph nodes (MLNs) of mice with DSS-induced acute colitis. Moreover, we speculated that IL-33 would promote the Treg or Breg responses leading to the attenuation of DSS-induced chronic colitis. So, we...
13 CitationsSource
#1Loris Riccardo Lopetuso (Case Western Reserve University)H-Index: 28
#2Carlo De Salvo (Case Western Reserve University)H-Index: 10
Last. Theresa T. Pizarro (Case Western Reserve University)H-Index: 46
view all 13 authors...
Defective and/or delayed wound healing has been implicated in the pathogenesis of several chronic inflammatory disorders, including inflammatory bowel disease (IBD). The resolution of inflammation is particularly important in mucosal organs, such as the gut, where restoration of epithelial barrier function is critical to reestablish homeostasis with the interfacing microenvironment. Although IL-33 and its receptor ST2/ILRL1 are known to be increased and associated with IBD, studies using animal ...
54 CitationsSource
#1Yongkui Li (HUST: Huazhong University of Science and Technology)H-Index: 6
#2Jie Shi (HUST: Huazhong University of Science and Technology)H-Index: 2
Last. Lin Wang (HUST: Huazhong University of Science and Technology)H-Index: 61
view all 9 authors...
Background Interleukin-33 (IL-33) participates in various types of diseases including cancers. Previous studies of this cytokine in cancers mainly focused on its regulation on immune responses by which IL-33 modulated cancer progression. The IL-33 triggered signals in cancer cells remain unclear.
29 CitationsSource
#1Xin Tang (HUST: Huazhong University of Science and Technology)H-Index: 4
#2Feng Wu (HUST: Huazhong University of Science and Technology)H-Index: 14
Last. Guanghai Yang (HUST: Huazhong University of Science and Technology)H-Index: 7
view all 6 authors...
The importance of understanding how interleukin-33 (IL-33) is regulated (particularly by miRs) is critical in IL-33 biology, and evidence of this in asthma pathology is limited. MicroRNA profiling of cells isolated from bronchoalveolar lavage of 14 asthmatic patients and 11 healthy controls revealed miR-200b and miR-200c were significantly reduced in asthmatic patients compared with healthy controls. The reduction was validated in two independent models of allergen-induced allergic airway inflam...
11 CitationsSource
#1Zhongyuan He (Nanjing Medical University)H-Index: 11
#2Zheng Li (Nanjing Medical University)H-Index: 21
Last. Zekuan Xu (Nanjing Medical University)H-Index: 33
view all 17 authors...
Increasing evidence indicates that dysregulation of microRNAs (miRNAs) plays a crucial role in human malignancies. Here, we showed that microRNA-422a (miR-422a) expression was dramatically downregulated in gastric cancer (GC) samples and cell lines compared with normal controls, and that its expression level was inversely related to tumor size and depth of infiltration. Functional studies revealed that the overexpression of miR-422a in GC tumor cells suppressed cell proliferation and migration, ...
30 CitationsSource
Background The aim of this study is to find the potential miRNA expression signature capable of predicting survival time for cervical squamous cell carcinoma (CSCC) patients. Methods The expression of 332 miRNAs was measured in 131 (Training cohort) and 130 (Validation cohort) patients with CSCC in the Cancer Genome Atlas (TCGA) data portal. The miRNA expression signature was identified by Cox Proportion Hazard regression model to the Training data set, and subsequently validated in an independe...
6 CitationsSource
#1Markus Gwiggner (University of Southampton)H-Index: 2
#2Rocio T. Martinez-Nunez (University of Southampton)H-Index: 13
Last. Tilman Sanchez-Elsner (University of Southampton)H-Index: 27
view all 8 authors...
Interleukin-13 (IL-13) is an important Type 2 T helper (Th2) cytokine, controlling biological functions in epithelium and has been linked to asthma, atopic dermatitis and ulcerative colitis (UC). Interleukin-13 signals through IL-13 receptor α-1 (IL13RA1 (gene) and IL13Rα1 (protein)), a receptor that can be regulated by microRNAs (miRs). MicroRNAs are small non-coding single-stranded RNAs with a role in several pathologies. However, their relevance in the pathophysiology of UC, a chronic inflamm...
25 CitationsSource
Cited By9
Newest
miR-128-3p is reported to involve in pathogenesis of several autoimmune diseases, yet the role of miR-128-3p in inflammatory bowel disease (IBD) remains unknown. To investigate miR-128-3p in IBD, experimental colitis animal model was generated by 2,4,6-Trinitrobenzenesulfonic acid solution (TNBS). miR-128-3p agomir was used to overexpress miR-128-3p in rats. Histological assessment and myeloperoxidase activity were conducted to evaluate the TNBS-induced colitis. Effect of miR-128-3p overexpressi...
Source
#1Zhi-Wu Dong (SJTU: Shanghai Jiao Tong University)H-Index: 2
Last. Ke-Wen Zhao (SJTU: Shanghai Jiao Tong University)H-Index: 7
view all 11 authors...
Alzheimer’s disease (AD) is the most common neurodegenerative disease in the older adults. Although much effort has been made in the analyses of diagnostic biomarkers, such as amyloid-β, tau, and neurofilament light chain, identifying peripheral blood-based biomarkers is in extremely urgent need for their minimal invasiveness and more convenience. Here we characterized the miRNA profile by RNA sequencing in human serum exosomes from AD patients and healthy controls (HC) to investigate its potent...
1 CitationsSource
#1Razieh DehghanH-Index: 1
#2Rezvan NajafiH-Index: 19
Last. Razieh AminiH-Index: 10
view all 9 authors...
Cross-talk among inflammation and colorectal cancer cells is chiefly reported through a complex of cytokines, chemokines, and growth factors. MicroRNA performs strategic roles in controlling a variety of signaling cascades. miR-34a is known as a master regulator of tumor suppression. Combined application of different miRNA-based agents and chemotherapeutic drugs has been used to augment drug sensitivity and may reinforce the antitumor effect. A lot of studies specify a substantial increase in th...
1 CitationsSource
#1Diego Marques (UFPA: Federal University of Pará)H-Index: 2
#2Layse Raynara Ferreira-Costa (UFRN: Federal University of Rio Grande do Norte)H-Index: 1
Last. Ândrea Ribeiro-dos-Santos (UFPA: Federal University of Pará)H-Index: 22
view all 12 authors...
The aberrant expression of microRNAs in known to play a crucial role in carcinogenesis. Here, we evaluated the miRNA expression profile of sigmoid colon cancer (SCC) compared to adjacent-to-tumor (ADJ) and sigmoid colon healthy (SCH) tissues obtained from colon biopsy extracted from Brazilian patients. Comparisons were performed between each group separately, considering as significant p-values 2. We found 20 differentially expressed miRNAs (DEmiRNAs) in all comparisons, two of which were shared...
1 CitationsSource
#1Yu Zhu (Bengbu Medical College)H-Index: 1
#2Yan Shi (Bengbu Medical College)H-Index: 1
Last. Zhenzeng Ma (Bengbu Medical College)H-Index: 1
view all 5 authors...
RING finger protein 8 (RNF8) is an E3 ligase that is pivotal for DNA repair. However, the role of RNF8 in ulcerative colitis (UC) remains unclear. The aim of this study is to investigate the effect and the mechanism of RNF8 on UC model induced by trinitrobenzene sulfonic acid (TNBS) in mice. Lentiviruses overexpressing RNF8 were injected into mice after the induction of UC. The histopathologic changes in colon tissues were assessed by hematoxylin and eosin staining. The mRNA level of RNF8 was de...
2 CitationsSource
Nerve Growth Factor (NGF) and its high-affinity receptor tropomyosin receptor kinase A (TRKA) increase their expression during the progression of epithelial ovarian cancer (EOC), promoting cell proliferation and angiogenesis through several oncogenic proteins, such as c-MYC and vascular endothelial growth factor (VEGF). The expression of these proteins is controlled by microRNAs (miRs), such as miR-145, whose dysregulation has been related to cancer. The aims of this work were to evaluate in EOC...
2 CitationsSource
Environmental factors contribute to autoimmune disease manifestation, and as regarded today, AhR has become an important factor in studies of immunomodulation. Besides immunological aspects, AhR also plays a role in pharmacological, toxicological and many other physiological processes such as adaptive metabolism. In recent years, epigenetic mechanisms have provided new insight into gene regulation and reveal a new contribution to autoimmune disease pathogenesis. DNA methylation, histone modifica...
3 CitationsSource
#2Tao Sun (ZJNU: Zhejiang Chinese Medical University)
Ulcerative colitis (UC) is one of the inflammatory bowel diseases (IBD) characterized by occurrence in the rectum and sigmoid colon of young adults. However, the functional roles of transcription factors (TFs) and their regulating target genes and pathways are not fully known in ulcerative colitis (UC). In this study, we collected gene expression data to identify differentially expressed TFs (DETFs). We found that differentially expressed genes (DEGs) were significantly enriched in the target ge...
Source