Association of SIRT-1, T helper 17-associated gene and Antimicrobial Peptides gene in Inflammatory Bowel Disease Patients
¹Cairo University, Cairo; ²Suez Canal University. Ismailia; ³Fayoum University, Al Fayoum; ^Misr University for Science and Technology, Giza. Egypt
*Corresponding author: Dina Sabry Abd El Fatah, Professor of Medical Biochemistry and Molecular Biology of the Cairo University, Egypt. E-mail: firstname.lastname@example.org
Published: September 16, 2017. doi: 10.21103/Article7(3)_OA7
The aim: of this study was to assess the expression of Th17-associated gene, AMPs genes and SIRT-1 protein in patients with inflammatory bowel disease (IBD).
Material and Methods: We studied a group of 20 IBD patients, together with 20 subjects served as controls. Colonoscopy, terminal ileoscopy, and colonoscopic biopsy were performed for histopathology diagnosis, and quantitative gene expression of Th17-associated gene, CAMP, Elafin and SLPI by real-time PCR. SIRT-1 protein level expression was assessed by western blot.
Results: The expression of the four studied genes—elafin, SLPI, CAMP and Th17-associated gene—by relative quantification was higher in the patient group than in the control group. A statistically significant positive correlation was found between SLPI and elafin in the patient group (r= 0.8325 P<0.001). A statistically significant positive correlation was reported as well between CAMP levels and elafin levels in the patient group (r=0.6842, P<0.001). In addition, CAMP levels had a positive correlation with SLPI levels in the patient group (r=0.6373, P<0.001). The highest expression of SIRT-1 was found in severe cases of IBD and the lowest expression was demonstrated in control subjects. A statistically significant positive correlation was detected between IL-17 levels and SIRT-1 levels in the patient group (r=0.7822, P<0.001).
Conclusion: A high expression of Th17-associated gene and AMPs gene has a significant impact on clinical assessment of patients with IBD. SIRT may participate in the progression of IBD.
1. Molodecky NA, Soon IS, Rabi DM, Ghali WA, Ferris M, Chernoff G, et al. Increasing incidence and prevalence of the inflammatory bowel diseases with time, based on systematic review. Gastroenterology. 2012;142(1):46–54 e42. doi: 10.1053/j.gastro.2011.10.001.
2. Franke A, McGovern DP , Barrett JC, Wang K, Radford-Smith GL, Ahmad T, et al. Genome-wide meta-analysis increases to 71 the number of confirmed Crohn’s disease susceptibility loci. Nat Genet. 2010;42(12):1118-25. doi: 10.1038/ng.717.
3. Anderson CA, Boucher G, Lees CW, Franke A, D'Amato M, Taylor KD, et al. Meta-analysis identifies 29 additional ulcerative colitis risk loci, increasing the number of confirmed associations to 47. Nat Genet. 2011;43(3):246–52. doi: 10.1038/ng.764.
4. Graham DB, Xavier RJ. From genetics of inflammatory bowel disease towards mechanistic insights. Trends Immunol. 2013;34(8):371-8. doi: 10.1016/j.it.2013.04.001.
5. Nutsch KM, Hsieh C-S. T cell tolerance and immunity to commensal bacteria. Curr Opin Immunol. 2012; 24(4):385–91. doi: 10.1016/j.coi.2012.04.009
6. Neurath MF, Finotto S, Glimcher LH. The role of Th1/Th2 polarization in mucosal immunity. Nat Med. 2002;8(6):567–73.
7. Shale M, Ghosh S. Beyond TNF, Th1 and Th2 in inflammatory bowel disease. Gut. 2008;57(10):1349–51. doi: 10.1136/gut.2008.151563.
8. Brand S. Crohn's disease: Th1, Th17 or both? The change of a paradigm: new immunological and genetic insights implicate Th17 cells in the pathogenesis of Crohn's disease. Gut. 2009; 58(8):1152–67. doi: 10.1136/gut.2008.163667.
9. Di Sabatino A, Biancheri P, Rovedatti L, MacDonald, TT, Corazza GR. New pathogenic paradigms in inflammatory bowel disease. Inflamm Bowel Dis. 2012; 18(2): 368–71. doi: 10.1002/ibd.21735.
10. Cunliffe RN, Mahida YR. Expression and regulation of antimicrobial peptides in the gastrointestinal tract. J Leukoc Biol. 2004; 75(1):49-58.
11. Arijs I, De Hertogh G, Lemaire K, Quintens R, Van Lommel L, Van Steen K, et al. Mucosal gene expression of antimicrobial peptides in inflammatory bowel disease before and after first infliximab treatment. PLoS ONE. 2009; 4(11): e7984. doi: 10.1371/journal.pone.0007984.
12. Peyrin-Biroulet L, Beisner J, Wang G, Nuding S, Oommen ST, Kelly D, et al. Peroxisome proliferator-activated receptor gamma activation is required for maintenance of innate antimicrobial immunity in the colon. Proc Natl Acad Sci USA. 2010;107(19):8772-7. doi: 10.1073/pnas.0905745107.
13. Noble CL, Abbas AR, Cornelius J, Lees CW, Ho GT, Toy K, et al. Regional variation in gene expression in the healthy colon is dysregulated in ulcerative colitis. Gut. 2008;57(10):1398–405. doi: 10.1136/gut.2008.148395.
14. Granlund AV, Beisvag V, Torp SH, Flatberg A, Kleveland PM, Ostvik AE, et al. Activation of REG family proteins in colitis. Scand J Gastroenterol. 2011; 46(11):1316–23. doi: 10.3109/00365521.2011.605463.
15. Simms LA, Doecke JD, Walsh MD, Huang N, Fowler EV, Radford-Smith GL. Reduced alpha-defensin expression is associated with inflammation and not NOD2 mutation status in ileal Crohn’s disease. Gut. 2008; 57(7):903–10. doi: 10.1136/gut.2007.142588.
16. LaPointe LC, Dunne R, Brown GS, Worthley DL, Molloy PL, Wattchow D, et al. Map of differential transcript expression in the normal human large intestine. Physiol Genomics. 2008;33(1):50–64.
17. Wątroba M, Szukiewicz D. The role of sirtuins in aging and age-related diseases. Adv Med Sci. 2015;61(1):52–62. doi: 10.1016/j.advms.2015.09.003.
18. Terauchi K, Kobayashi H, Yatabe K, Yui N, Fujiya H, Niki H, Musha H, Yudoh K. The NAD-Dependent Deacetylase Sirtuin-1 Regulates the Expression of Osteogenic Transcriptional Activator Runt-Related Transcription Factor 2 (Runx2) and Production of Matrix Metalloproteinase (MMP)-13 in Chondrocytes in Osteoarthritis. Int J Mol Sci. 2016;17(7). pii: E1019. doi: 10.3390/ijms17071019.
19. Brahmania M, Bernstein CN. Physician global assessments or blood tests do not predict mucosal healing in ulcerative colitis. Can J Gastroenterol Hepatol. 2014;28(6):325-9.
20. Isene R, Bernklev T, Høie O, Munkholm P, Tsianos E, Stockbrügger R et al. Extraintestinal manifestations in Crohn's disease and ulcerative colitis: results from a prospective, population-based European inception cohort. Scand J Gastroenterol. 2015; 50(3):300-5. doi: 10.3109/00365521.2014.991752
21. Dignass A, Eliakim R, Magro F, Maaser C, Chowers Y, Geboes K, et al. [Second European evidence-based Consensus on the diagnosis and management of ulcerative colitis Part 1: Definitions and diagnosis (Spanish version)]. Rev Gastroenterol Mex. 2014;79(4):263-89. doi: 10.1016/j.rgmx.2014.10.001. [Article in Spanish]
22. Lennard-Jones JE, Shivananda S. Clinical uniformity of inflammatory bowel disease a presentation and during the first year of disease in the north and south of Europe. EC-IBD Study Group. Eur J Gastroenterol Hepatol. 1997;9(4):353-9.
23. Sands BE. From symptom to diagnosis: clinical distinctions among various forms of intestinal inflammation. Gastroenterology. 2004;126(6):1518-32.
24. Van Assche G, Dignass A, Panes J, Beaugerie L, Karagiannis J, Allez M, et al. The second European evidence-based Consensus on the diagnosis and management of Crohn's disease: Definitions and diagnosis. J Crohns Colitis. 2010;4(1):7-27. doi: 10.1016/j.crohns.2009.12.003.
25. Melmed GY, Elashoff R, Chen GC, Nastaskin I, Papadakis KA, Vasiliauskas EA, et al. Predicting a change in diagnosis from ulcerative colitis to Crohn's disease: a nested, case-control study. Clin Gastroenterol Hepatol. 2007; 5(5):602-8.
26. Ricanek P, Lunde LK, Frye SA, Støen M, Nygård S, Morth JP, et al. Reduced expression of aquaporins in human intestinal mucosa in early stage inflammatory bowel disease. Clin Exp Gastroenterol. 2015;8:49-67. doi: 10.2147/CEG.S70119.
27. Geboes K, De Hertogh G. Indeterminate colitis. Inflamm Bowel Dis, 2003;9(5):324-31.
28. Doss M, White MR, Tecle T, Hartshorn KL. Human defensins and LL-37 in mucosal immunity. J Leukoc Biol. 2010;87(1):79–92. doi: 10.1189/jlb.0609382.
29. Pütsep K, Carlsson G, Boman H, Andersson M. Deficiency of antibacterial peptides in patients with morbus Kostmann: an observation study. Lancet. 2002;360(9340):1144–9.
30. Iimura M, Gallo RL, Hase K, Miyamoto Y, Eckmann L, Kagnoff MF. Cathelicidin mediates innate intestinal defense against colonization with epithelial adherent bacterial pathogens. J Immunol. 2005; 174(8):4901–7
31. Schauber J, Rieger D, Weiler F, Wehkamp J, Eck M, Fellermann K. et al. Heterogeneous expression of human cathelicidin hCAP18/LL-37 in inflammatory bowel diseases. Eur J Gastroenterol Hepatol. 2006; 18(6):615–21.
32. Medina C, Radomski MW. Role of matrix metalloproteinases in intestinal inflammation. J Pharmacol Exp Ther. 2006 Sep 318(3):933-8.
33. Wiesner J, Vilcinskas A. Antimicrobial peptides: the ancient arm of the human immune system. Virulence. 2010;1(5):440–64. doi: 10.4161/viru.1.5.12983.
34. Schmid M, Fellermann K, Fritz P, Wiedow O, Stange EF, Wehkamp J. Attenuated induction of epithelial and leukocyte serine antiproteases elafin and secretory leukocyte protease inhibitor in Crohn's disease. J Leukoc Biol .2007;81(4):907-15.
35. Masuda K, Kamimura T, Watanabe K, Suga T, Kanesaki M, Takeuchi A, et al. Pharmacological activity of the C-terminal and N-terminal domains of secretory leukoprotease inhibitor in vitro. Br J Pharmacol. 1995; 115(6):883-8.
36. Sallenave JM. The role of secretory leukocyte proteinase inhibitor and elafin (elastase-specific inhibitor/skin-derived antileukoprotease) as alarm antiproteinases in inflammatory lung disease. Respir Res. 2000; 1(2):87-92.
37. Bergenfeldt M, Nyström M, Bohe M, Lindström C, Polling A, Ohlsson K. Localization of immunoreactive secretory leukocyte protease inhibitor (SLPI) in intestinal mucosa. J Gastroenterol. 1996; 31(1):18-23.
38. Suzuki Y, Furukawa M, Abe J, Kashiwagi M, Hirose S. Localization of porcine trappin-2 (SKALP/elafin) in trachea and large intestine by in situ hybridization and immunohistochemistry. Histochem Cell Biol. 2000; 114(1):15-20.
39. Okahara S, Arimura Y, Yabana T, Kobayashi K, Gotoh A, Motoya S, et al. Inflammatory gene signature in ulcerative colitis with cDNA macroarray analysis. Aliment Pharmacol Ther. 2005; 21(9):1091-7.
40. Hiemstra PS, Maassen RJ, Stolk J, Heinzel-Wieland R, Steffens GJ, Dijkman JH. Antibacterial activity of antileukoprotease. Infect Immun, 1996;64(11):4520-4.
41. Shugars DC. Endogenous mucosal antiviral factors of the oral cavity. J Infect Dis. 1999;179 Suppl 3:S431-5.
42. Simpson AJ, Maxwell AI, Govan JR, Haslett C, Sallenave JM. Elafin (elastase-specific inhibitor) has anti-microbial activity against gram-positive and gram-negative respiratory pathogens. FEBS Lett.1999; 452(3):309-13.
43. Doumas S, Kolokotronis A, Stefanopoulos P. Anti-inflammatory and antimicrobial roles of secretory leukocyte protease inhibitor. Infect Immun. 2005;73(3):1271-4.
44. Schmid M, Fellermann K, Fritz P, Wiedow O, Stange EF, Wehkamp J. Attenuated induction of epithelial and leukocyte serine antiproteases elafin and secretory leukocyte protease inhibitor in Crohn’s disease. J Leukoc Biol. 2007; 81(4):907–15.
45. Iwakura Y, Ishigame H, Saijo S, Nakae S. Functional specialization of interleukin-17 family members. Immunity. 2011;34(2):149-62. doi: 10.1016/j.immuni.2011.02.012.
46. Jiang W, Su J, Zhang X, Cheng X, Zhou J, Shi R, et al. Elevated levels of Th17 cells and Th17-related cytokines are associated with disease activity in patients with inflammatory bowel disease. Inflamm Res. 2014; 63(11):943-50. doi: 10.1007/s00011-014-0768-7.
47. Ford J, Jiang M, Milner J. Cancer-specific functions of SIRT1 enable human epithelial cancer cell growth and survival. Cancer Res. 2005;65(22):10457–63.
48. Rajendrasozhan S, Yang SR, Kinnula VL, Rahman I. SIRT1, an antiinflammatory and antiaging protein, is decreased in lungs of patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2008;177(8):861–70. doi: 10.1164/rccm.200708-1269OC.
49. Sharma M, Mohapatra J, Wagh A, Patel HM, Pandey D, Kadam S, et al. Involvement of TACE in colon inflammation: a novel mechanism of regulation via SIRT-1 activation. Cytokine. 2014;66(1):30-9. doi: 10.1016/j.cyto.2013.12.010.
50. Lukás K. [Idiopathic inflammatory bowel disease--prediction and treatment]. Cas Lek Cesk 2011; 150(6):315-20. [Article in Czech]
The fully formatted PDF version is available.
International Journal of Biomedicine. 2017;7(3):196-203. ©2017 International Medical Research and Development Corporation. All rights reserved.