Contribution of NOTCH signaling pathway along with TNF-? in the intestinal inflammation of ulcerative colitis
Gastroenterology and Hepatology from Bed to Bench,
Aim: The aim of this study was to determine gene expression levels of TNF-?, NOTCH1, and HES1 in patients with UC.
Background: Intestinal inflammation and epithelial injury are the leading actors of inflammatory bowel disease (IBD), causing an excessive expression of pro-inflammatory cytokines such as TNF-?. Also, target genes of NOTCH signaling are involved in the regulation of intestinal homeostasis. Previous studies have demonstrated that TNF-? increases in ulcerative colitis (UC) patients, but the relationship between TNF-? and NOTCH signaling pathway in UC etiopathology needs further study.
Methods: Twelve active UC patients and twelve healthy controls were enrolled in this study. RNA was extracted and the mRNA expression levels of TNF-?, NOTCH1, and HES1 were examined using real-time PCR analyses. Further, transcriptome data deposited in Gene Expression Omnibus (GEO) database were analyzed to detect the differential expression of TNF superfamily and NOTCH1 gene in IBD patients. Finally, the interaction of TNF-? and NOTCH signaling was obtained from The SIGnaling Network Open Resource 2.0 (SIGNOR 2.0) database.
Results: The transcription levels of TNF-?, NOTCH1, and HES1 genes were significantly elevated in UC patients compared with control (p < 0.05). In addition, GEO results confirmed our expression results. SIGNOR analysis showed that TNF-? interacts with NOTCH signaling components.
Conclusion: Based on our data, we observed that NOTCH1 and HES1 in co-operation of TNF-?, may play an important role in pathogenesis of UC. The members of NOTCH signaling pathway can be ideal candidates to target the therapy of IBD.
Keywords: Ulcerative colitis, TNF-?, NOTCH signaling, HES1.
(Please cite as: Ghorbaninejad M, Heydari R, Mohammadi P, Shahrokh SH, Haghazali M, Khanabadi B, et al. Contribution of NOTCH signaling pathway along with TNF-? in intestinal inflammation of ulcerative colitis. Gastroenterol Hepatol Bed Bench 2019;12(Suppl.1):S80-S86).
- Ulcerative colitis
- NOTCH signaling
How to Cite
Okamoto R, Watanabe M. Role of epithelial cells in the pathogenesis and treatment of inflammatory bowel disease. Journal of gastroenterology. 2016;51(1):11-21.
Khor B, Gardet A, Xavier RJ. Genetics and pathogenesis of inflammatory bowel disease. Nature. 2011;474(7351):307.
Xavier R, Podolsky D. Unravelling the pathogenesis of inflammatory bowel disease. Nature. 2007;448(7152):427.
Suzuki M, Nagaishi T, Yamazaki M, Onizawa M, Watabe T, Sakamaki Y, et al. Myosin light chain kinase expression induced via tumor necrosis factor receptor 2 signaling in the epithelial cells regulates the development of colitis-associated carcinogenesis. PLoS One. 2014;9(2):e88369.
Kim JH, Hwang SW, Koh J, Chun J, Lee C, Im JP, et al. Inactive Rhomboid Protein 2 Mediates Intestinal Inflammation by Releasing Tumor Necrosis Factor–α. Inflammatory bowel diseases. 2019.
Vooijs M, Liu Z, Kopan R. Notch: architect, landscaper, and guardian of the intestine. Gastroenterology. 2011;141(2):448-59.
Hansson EM, Lendahl U, Chapman G, editors. Notch signaling in development and disease. Seminars in cancer biology; 2004: Elsevier.
Boulter L, Govaere O, Bird TG, Radulescu S, Ramachandran P, Pellicoro A, et al. Macrophage-derived Wnt opposes Notch signaling to specify hepatic progenitor cell fate in chronic liver disease. Nature medicine. 2012;18(4):572.
de la Pompa JL, Epstein JA. Coordinating tissue interactions: Notch signaling in cardiac development and disease. Developmental cell. 2012;22(2):244-54.
Lasky JL, Wu H. Notch signaling, brain development, and human disease. Pediatric research. 2005;57(5 Part 2):104R.
Shih I-M, Wang T-L. Notch signaling, γ-secretase inhibitors, and cancer therapy. Cancer research. 2007;67(5):1879-82.
Murano T, Okamoto R, Ito G, Nakata T, Hibiya S, Shimizu H, et al. Hes1 promotes the IL-22-mediated antimicrobial response by enhancing STAT3-dependent transcription in human intestinal epithelial cells. Biochemical and biophysical research communications. 2014;443(3):840-6.
Noah TK, Shroyer NF. Notch in the intestine: regulation of homeostasis and pathogenesis. Annual review of physiology. 2013;75:263-88.
Jiao Z, Wang W, Ma J, Wang S, Su Z, Xu H. Notch signaling mediates TNF-α-induced IL-6 production in cultured fibroblast-like synoviocytes from rheumatoid arthritis. Clinical and Developmental Immunology. 2011;2012.
Ando K, Kanazawa S, Tetsuka T, Ohta S, Jiang X, Tada T, et al. Induction of Notch signaling by tumor necrosis factor in rheumatoid synovial fibroblasts. Oncogene. 2003;22(49):7796.
Meyfour A, Ansari H, Pahlavan S, Mirshahvaladi S, Rezaei-Tavirani M, Gourabi H, et al. Y chromosome missing protein, TBL1Y, may play an important role in cardiac differentiation. Journal of proteome research. 2017;16(12):4391-402.
Bsat M, Chapuy L, Rubio M, Wassef R, Richard C, Schwenter F, et al. Differential pathogenic Th17 profile in mesenteric lymph nodes of Crohn’s disease and ulcerative colitis patients. Frontiers in immunology. 2019;10:1177.
Gao Y, Theng SS, Mah W-C, Lee CG. Silibinin down-regulates FAT10 and modulate TNF-α/IFN-γ-induced chromosomal instability and apoptosis sensitivity. Biology open. 2015;4(8):961-9.
Kucharzik T, Maaser C, Lügering A, Kagnoff M, Mayer L, Targan S, et al. Recent understanding of IBD pathogenesis: implications for future therapies. Inflammatory bowel diseases. 2006;12(11):1068-83.
Atreya R, Neurath MF. IBD pathogenesis in 2014: Molecular pathways controlling barrier function in IBD. Nature reviews Gastroenterology & hepatology. 2015;12(2):67.
Schmitt H, Billmeier U, Dieterich W, Rath T, Sonnewald S, Reid S, et al. Expansion of IL-23 receptor bearing TNFR2+ T cells is associated with molecular resistance to anti-TNF therapy in Crohn’s disease. Gut. 2019;68(5):814-28.
Zheng X, Tsuchiya K, Okamoto R, Iwasaki M, Kano Y, Sakamoto N, et al. Suppression of hath1 gene expression directly regulated by hes1 via notch signaling is associated with goblet cell depletion in ulcerative colitis. Inflammatory bowel diseases. 2011;17(11):2251-60.
Kawamoto A, Nagata S, Anzai S, Takahashi J, Kawai M, Hama M, et al. Ubiquitin D is Upregulated by Synergy of Notch Signalling and TNF-α in the Inflamed Intestinal Epithelia of IBD Patients. Journal of Crohn's and Colitis. 2018;13(4):495-509.
- Abstract Viewed: 70 times
- PDF Downloaded: 28 times