EXPRESSION OF INNATE IMMUNE RECEPTORS AND TRANSCRIPTIONAL REGULATION OF T-HELPER CELLS IN EXPERIMENTAL ILEITIS AND CONDUCT OF THE SIMVASTATIN AND ARIL-1

DOI: https://doi.org/None

A.S. Zherebiatiev, A.M. Kamyshny, V.A. Kamyshnaya Zaporozhye State Medical University, Mayakovsky avenue 26, Zaporozhye, 69035, Ukraine

Introduction. The pathogenesis of inflammatory bowel disease is complex and multifactorial. Studies have led to the current concept that the T-helper cells are components of the adaptive immune response whereas Toll-like receptors, NOD-like-receptors, RIG-I-like receptors represent key mediators of innate host defense in the intestine, and they are involved in maintaining mucosal as well as commensal homeostasis. The aim of the study. We studied the possibility of simvastatin and antagonist of receptors of interleukin-1 for correction of experimental ileitis in rats with afocus on the expression studies of Toll-like receptor 2 (TLR2), Toll-like receptor 4 (TLR4), NOD2, RIG-I and transcription factors T-bet, GATA-3, RORγt and Foxp3 with lymphocytes of small intestine. Methods. Experiments were carried out on male Wistar rats aged of 5–7 months. The immunopositive lymphocytes were determined by using both of a direct and indirect immunofluorescence technique and a monoclonal rat antibody. Results. The study of serial sections of ileum showed that the development of acute and chronic ileitis was accompanied with onedirected tendency on increasing of total number of TLR2+ lymphocytes and decreasing of total number of TLR4+ and Foxp3+ lymphocytes in lymphoid structures of ileum.The administrations of Simvastatin and ARIL-1 in experimental animals during the development of experimental pathology was accompanied by decrease of RORγt+- and T-bet+ lymphocytes,and increasing of total number of Foxp3+ lymphocytes. Conclusion. Simvastatin and antagonist of receptors of interleukin-1 seemed to be beneficial in indomethacin-induced ileitis model in rats through the modulation of the expression of pattern recognition receptors on lymphocytes and balance between different T-helper cell subsets of the small intestine.
Keywords: 
ileitis, pattern recognition receptors, antagonist of receptors of interleukin-1 (ARIL-1), simvastatin

Список литературы: 
  1. Sartor R.B. Mechanisms of disease: pathogenesis of Crohn’s disease and ulcerative colitis. Nat. Clin. Pract. Gastroenterol. Hepatol. 2006; 3 (7): 390–407.
  2. Chao K., Zhong B.H., Zhang S.H., Gong X.R., Yao J.Y., Chen M.H. Imbalance of CD4(+) T cell subgroups in ulcerative colitis. Zhonghua. Yi Xue Za Zhi. 2011; 91 (23): 1605–8.
  3. Izcue A., Coombes J.L., Powrie F. Regulatory T cells suppress systemic and mucosal immune activation to control intestinal inflammation. Immunol. Rev. 2006; 212: 256–71.
  4. Leung B.P., Sattar N., Crilly A., Prach M., McCarey D.W., Payne H., Madhok R., Campbell C., Gracie J.A., Liew F.Y., McInnes I.B. A novel anti-inflammatory role for simvastatin in inflammatory arthritis. J. Immunol. 2003; 170 (3): 1524–30.
  5. Grip O., Janciauskiene S. Atorvastatin reduces plasma levels of chemokine (CXCL10) in patients with Crohn’s disease. PLoS One. 2009; 4 (5): 5263.
  6. Thompson R.C., Dripps D.J., Eisenberg S.P. Interleukin-1 receptor antagonist (IL-1ra) as a probe and as a treatment for IL-1 mediated disease. Int. J. Immunopharmacol. 1992; 14 (3): 475–80.
  7. Nandi J., Saud B., Zinkievich J.M., Yang Z.J., Levine R.A. TNF-alpha modulates iNOS expression in an experimental rat model of indomethacin-induced jejunoileitis. Mol. Cell. Biochem. 2010; 336 (1–2): 17–24.
  8. Yamada T., Deitch E., Specian R.D., Perry M.A., Sartor R.B., Grisham M.B. Mechanisms of acute and chronic intestinal inflammation induced by indomethacin. Inflammation. 1993; 17 (6): 641–62.
  9. Tanaka K. Expression of Toll-like receptors in the intestinal mucosa of patients with inflammatory bowel disease. Expert Rev. Gastroenterol. Hepatol. 2008; 2 (2): 193–6.
  10. Cario E. Barrier-protective function of intestinal epithelial Toll-like receptor 2. Mucosal Immunol. 2008; 1: 62–6.
  11. Reynolds J.M., Pappu B.P., Peng J., Martinez G.J., Zhang Y., Chung Y., Ma L., Yang X.O., Nurieva R.I., Tian Q., Dong C. Toll-like receptor 2 signaling in CD4(+) T lymphocytes promotes T helper 17 responses and regulates the pathogenesis of autoimmune disease. Immunity. 2010; 32 (5): 692–702.
  12. Wang X., Li M., Zheng H., Muster T., Palese P., Beg A.A., Garcia-Sastre A. Influenza A virus NS1 protein prevents activation of NF-kappaB and induction of alpha/beta interferon. J. Virol. 2000; 74 (24): 11566–73.
  13. Negishi H., Yanai H., Nakajima A., Koshiba R., Atarashi K., Matsuda A., Matsuki K., Miki S., Doi T., Aderem A., Nishio J., Smale ST., Honda K., Taniguchi T. Cross-interference of RLR and TLR signaling pathways modulates antibacterial T cell responses. Nat. Immunol. 2012; 13 (7): 659–66.
  14. Neurath M.F., Weigmann B., Finotto S., Glickman J., Nieuwenhuis E., Iijima H., Mizoguchi A., Mizoguchi E., Mudter J., Galle P.R., Bhan A., Autschbach F., Sullivan B.M., Szabo S.J., Glimcher L.H., Blumberg R.S. The transcription factor T-bet regulates mucosal T cell activation in experimental colitis and Crohn’s disease. J. Exp. Med. 2002; 195 (9): 1129–43.
  15. Dambacher J., Beigel F., Zitzmann K., De Toni E.N., Göke B., Diepolder H.M., Auernhammer C.J., Brand S. The role of the novel Th17 cytokine IL-26 in intestinal inflammation. Gut. 2009; 58 (9): 1207–17.
  16. Ohtani K., Ohtsuka Y., Ikuse T., Baba Y., Yamakawa Y., Aoyagi Y., Fujii T., Kudo T., Nagata S., Shimizu T. Increased mucosal expression of GATA-3 and STAT-4 in pediatric ulcerative colitis. Pediatr. Int. 2010; 52 (4): 584–9.
  17. Bamias G., Martin C., Mishina M., Ross W.G., Rivera-Nieves J., Marini M., Cominelli F. Proinflammatory effects of TH2 cytokines in a murine model of chronic small intestinal inflammation. Gastroenterology. 2005; 28 (3): 654–66.
  18. Spits H., Cupedo T. Innate lymphoid cells: emerging insights in development, lineage relationships, and function. Annu. Rev. Immunol. 2012; 30: 647–75.
  19. Eberl G. Inducible lymphoid tissues in the adult gut: recapitulation of a fetal developmental pathway? Nat. Rev. Immunol. 2005; 5 (5): 413–20.
  20. Sonnenberg G.F., Monticelli L.A., Alenghat T., Fung T.C. Innate lymphoid cells promote anatomical containment of lymphoid-resident commensal bacteria. Science. 2012; 336 (6086): 1321–5.
  21. Ciccia F., Accardo-Palumbo A., Alessandro R., Rizzo A., Principe S., Peralta S., Raiata F., Giardina A., De Leo G., Triolo G. Interleukin-22 and interleukin-22-producing NKp44+ natural killer cells in subclinical gut inflammation in ankylosing spondylitis. Arthritis Rheum. 2012; 64 (6): 1869–78.
  22. Geremia A., Arancibia-Cárcamo C.V., Fleming M.P., Rust N., Singh B., Mortensen N.J., Travis S.P., Powrie F. IL-23-responsive innate lymphoid cells are increased in inflammatory bowel disease. J. Exp. Med. 2011; 208 (6): 1127–33.