Treatment with novel AP-1 and NF-κB inhibitors restores the colonic endocrine cells to normal levels in rats with DSS-induced colitis

El-Salhy,Magdy; Umezawa,Kazuo

doi:10.3892/ijmm.2016.2481

Treatment with novel AP-1 and NF-κB inhibitors restores the colonic endocrine cells to normal levels in rats with DSS-induced colitis

Authors:
- Magdy El-Salhy
- Kazuo Umezawa
View Affiliations

Affiliations: Division of Gastroenterology, Department of Medicine, Stord Helse-Fonna Hospital, Stord, Norway, Department of Molecular Target Medicine, School of Aichi Medical University, School of Medicine, Nagakute, Aichi, Japan
Published online on: February 5, 2016 https://doi.org/10.3892/ijmm.2016.2481
Pages: 556-564
Copyright: © El-Salhy et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

The aim of this study was to determine the effects of two anti-inflammatory agents on the abnormalities in colonic endocrine cells in dextran sodium sulfate (DSS)-induced colitis. Colitis was induced in male Wistar rats (n=45) using DSS; a further 15 rats without colitis were included in a healthy control group. The animals with DSS-induced colitis were randomly divided into 3 treatment groups as follows: i) DSS group, rats were treated with 0.5 ml of 0.5% carboxymethyl cellulose (CMC); ii) DSS‑G group, rats were treated with 3-[(dodecylthiocarbonyl)‑methyl]‑glutarimide (DTCM‑G), a novel activator protein 1 (AP-1) inhibitor, 20 mg/kg in CMC; and iii) DSS‑Q group, rats were treated with dehydroxymethylepoxyquinomicin, a nuclear factor κB (NF-κB) inhibitor, 15 mg/kg in CMC. The treatments were administered intraperitoneally, twice daily for 5 days, after which the animals were sacrificed and tissue samples from the colon were immunostained for chromogranin A (CgA), serotonin, peptide YY (PYY), enteroglucagon, pancreatic polypeptide (PP), somatostatin, leukocytes, B/T lymphocytes, B lymphocytes, T lymphocytes, macrophages/monocytes and mast cells. The densities of these endocrine and immune cells were quantified by computer‑aided image analysis. The densities of CgA-, serotonin-, PYY- and enteroglucagon-producing cells were significantly higher, and those of PP- and somatostatin-producing cells were significantly lower in the DSS‑G, DSS‑Q and control groups than in the DSS group. The densities of all the immune cells were lower in the DSS‑G, DSS‑Q and control groups than in the DSS group. The densities of all endocrine cell types and immune cells in both the DSS groups treated with anti‑inflammatory agents were restored to control levels. In conclusion, our data demonstrate that there is an interaction between endocrine and immune cells during inflammation. This interaction with subsequent changes in endocrine cells is responsible for the clinical manifestation of colitis symptoms.

View Figures

View References

1	El-Salhy M, Danielsson A, Stenling R and Grimelius L: Colonic endocrine cells in inflammatory bowel disease. J Intern Med. 242:413–419. 1997. View Article : Google Scholar
2	El-Salhy M, Gundersen D, Hatlebakk JG and Hausken T: Chromogranin A cell density as a diagnostic marker for lymphocytic colitis. Dig Dis Sci. 57:3154–3159. 2012. View Article : Google Scholar : PubMed/NCBI
3	El-Salhy M, Gundersen D, Hatlebakk JG and Hausken T: High densities of serotonin and peptide YY cells in the colon of patients with lymphocytic colitis. World J Gastroenterol. 18:6070–6075. 2012. View Article : Google Scholar : PubMed/NCBI
4	El-Salhy M, Lomholt-Beck B and Gundersen TD: High chromogranin A cell density in the colon of patients with lymphocytic colitis. Mol Med Rep. 4:603–605. 2011.PubMed/NCBI
5	Moran GW, Pennock J and McLaughlin JT: Enteroendocrine cells in terminal ileal Crohn's disease. J Crohn's Colitis. 6:871–880. 2012. View Article : Google Scholar
6	Moran GW, Leslie FC and McLaughlin JT: Crohn's disease affecting the small bowel is associated with reduced appetite and elevated levels of circulating gut peptides. Clin Nutr. 32:404–411. 2013. View Article : Google Scholar
7	Besterman HS, Mallinson CN, Modigliani R, Christofides ND, Pera A, Ponti V, Sarson DL and Bloom SR: Gut hormones in inflammatory bowel disease. Scand J Gastroenterol. 18:845–852. 1983. View Article : Google Scholar : PubMed/NCBI
8	El-Salhy M, Mazzawi T, Gundersen D, Hatlebakk JG and Hausken T: The role of peptide YY in gastrointestinal diseases and disorders (review). Int J Mol Med. 31:275–282. 2013.Review. PubMed/NCBI
9	Hirotani Y, Mikajiri K, Ikeda K, Myotoku M and Kurokawa N: Changes of the peptide YY levels in the intestinal tissue of rats with experimental colitis following oral administration of mesalazine and prednisolone. Yakugaku Zasshi. 128:1347–1353. 2008. View Article : Google Scholar : PubMed/NCBI
10	Vona-Davis LC and McFadden DW: NPY family of hormones: clinical relevance and potential use in gastrointestinal disease. Curr Top Med Chem. 7:1710–1720. 2007. View Article : Google Scholar : PubMed/NCBI
11	El-Salhy M, Suhr O and Danielsson A: Peptide YY in gastrointestinal disorders. Peptides. 23:397–402. 2002. View Article : Google Scholar : PubMed/NCBI
12	Tari A, Teshima H, Sumii K, Haruma K, Ohgoshi H, Yoshihara M, Kajiyama G and Miyachi Y: Peptide YY abnormalities in patients with ulcerative colitis. Jpn J Med. 27:49–55. 1988. View Article : Google Scholar : PubMed/NCBI
13	Sciola V, Massironi S, Conte D, Caprioli F, Ferrero S, Ciafardini C, Peracchi M, Bardella MT and Piodi L: Plasma chromogranin a in patients with inflammatory bowel disease. Inflamm Bowel Dis. 15:867–871. 2009. View Article : Google Scholar
14	Bishop AE, Pietroletti R, Taat CW, Brummelkamp WH and Polak JM: Increased populations of endocrine cells in Crohn's ileitis. Virchows Arch A Pathol Anat Histopathol. 410:391–396. 1987. View Article : Google Scholar : PubMed/NCBI
15	Manocha M and Khan WI: Serotonin and GI Disorders: an update on clinical and experimental studies. Clin Transl Gastroenterol. 3:e132012. View Article : Google Scholar : PubMed/NCBI
16	Stoyanova II and Gulubova MV: Mast cells and inflammatory mediators in chronic ulcerative colitis. Acta Histochem. 104:185–192. 2002. View Article : Google Scholar : PubMed/NCBI
17	Yamamoto H, Morise K, Kusugami K, Furusawa A, Konagaya T, Nishio Y, Kaneko H, Uchida K, Nagai H, Mitsuma T, et al: Abnormal neuropeptide concentration in rectal mucosa of patients with inflammatory bowel disease. J Gastroenterol. 31:525–532. 1996. View Article : Google Scholar : PubMed/NCBI
18	Payer J, Huorka M, Duris I, Mikulecky M, Kratochvílová H, Ondrejka P and Lukác L: Plasma somatostatin levels in ulcerative colitis. Hepatogastroenterology. 41:552–553. 1994.PubMed/NCBI
19	Watanabe T, Kubota Y, Sawada T and Muto T: Distribution and quantification of somatostatin in inflammatory disease. Dis Colon Rectum. 35:488–494. 1992. View Article : Google Scholar : PubMed/NCBI
20	Koch TR, Carney JA, Morris VA and Go VL: Somatostatin in the idiopathic inflammatory bowel diseases. Dis Colon Rectum. 31:198–203. 1988. View Article : Google Scholar : PubMed/NCBI
21	Khan WI and Ghia JE: Gut hormones: emerging role in immune activation and inflammation. Clin Exp Immunol. 161:19–27. 2010.PubMed/NCBI
22	Margolis KG and Gershon MD: Neuropeptides and inflammatory bowel disease. Curr Opin Gastroenterol. 25:503–511. 2009. View Article : Google Scholar : PubMed/NCBI
23	Ota E, Takeiri M, Tachibana M, Ishikawa Y, Umezawa K and Nishiyama S: Synthesis and biological evaluation of molecular probes based on the 9-methylstreptimidone derivative DTCM-glutarimide. Bioorg Med Chem Lett. 22:164–167. 2012. View Article : Google Scholar
24	Shibasaki S, Yamashita K, Goto R, Wakayama K, Tsunetoshi Y, Zaitsu M, Igarashi R, Haga S, Ozaki M, Umezawa K and Todo S: Immunosuppressive effects of DTCM-G, a novel inhibitor of the mTOR downstream signaling pathway. Transplantation. 95:542–550. 2013. View Article : Google Scholar
25	Funakoshi T, Yamashita K, Ichikawa N, Fukai M, Suzuki T, Goto R, Oura T, Kobayashi N, Katsurada T, Ichihara S, et al: A novel NF-κB inhibitor, dehydroxymethylepoxyquinomicin, ameliorates inflammatory colonic injury in mice. J Crohn's Colitis. 6:215–225. 2012. View Article : Google Scholar
26	El-Salhy M, Umezawa K, Gilja OH, Hatlebakk JG, Gundersen D and Hausken T: Amelioration of severe TNBS induced colitis by novel AP-1 and NF-κB inhibitors in rats. Scientific World Journal. 2014:1–8. 2014. View Article : Google Scholar
27	Takeiri M, Tachibana M, Kaneda A, Ito A, Ishikawa Y, Nishiyama S, Goto R, Yamashita K, Shibasaki S, Hirokata G, et al: Inhibition of macrophage activation and suppression of graft rejection by DTCM-Glutarimide, a novel piperidine derived from the antibiotic 9-methylstreptimidone. Inflamm Res. 60:879–888. 2011. View Article : Google Scholar : PubMed/NCBI
28	Ishikawa Y, Tachibana M, Matsui C, Obata R, Umezawa K and Nishiyama S: Synthesis and biological evaluation on novel analogs of 9-methylstreptimidone, an inhibitor of NF-kappaB. Bioorg Med Chem Lett. 19:1726–1728. 2009. View Article : Google Scholar : PubMed/NCBI
29	Ueki S, Yamashita K, Aoyagi T, Haga S, Suzuki T, Itoh T, Taniguchi M, Shimamura T, Furukawa H, Ozaki M, et al: Control of allograft rejection by applying a novel nuclear factor-kappaB inhibitor, dehydroxymethylepoxyquinomicin. Transplantation. 82:1720–1727. 2006. View Article : Google Scholar
30	Matsumoto N, Ariga A, To-e S, Nakamura H, Agata N, Hirano S, Inoue J and Umezawa K: Synthesis of NF-kappaB activation inhibitors derived from epoxyquinomicin C. Bioorg Med Chem Lett. 10:865–869. 2000. View Article : Google Scholar : PubMed/NCBI
31	Umezawa N, Matsumoto N, Iwama S, Kato N and Higuchi T: Facile synthesis of peptide-porphyrin conjugates: towards artificial catalase. Bioorg Med Chem. 18:6340–6350. 2010. View Article : Google Scholar : PubMed/NCBI
32	El-Salhy M, Gilja OH, Gundersen D, Hatlebakk JG and Hausken T: Endocrine cells in the ileum of patients with irritable bowel syndrome. World J Gastroenterol. 20:2383–2391. 2014. View Article : Google Scholar : PubMed/NCBI
33	El-Salhy M, Gundersen D, Hatlebakk JG and Hausken T: Low-Grade inflammation in the rectum of patients with sporadic irritable bowel syndrome. Mol Med Rep. 7:1081–1085. 2013.PubMed/NCBI
34	Elson CO, Sartor RB, Tennyson GS and Riddell RH: Experimental models of inflammatory bowel disease. Gastroenterology. 109:1344–1367. 1995. View Article : Google Scholar : PubMed/NCBI
35	Low D, Nguyen DD and Mizoguchi E: Animal models of ulcerative colitis and their application in drug research. Drug Des Devel Ther. 7:1341–1357. 2013.PubMed/NCBI
36	Spiller R: Serotonin and GI clinical disorders. Neuropharmacology. 55:1072–1080. 2008. View Article : Google Scholar : PubMed/NCBI
37	Egger M, Beer AG, Theurl M, Schgoer W, Hotter B, Tatarczyk T, Vasiljevic D, Frauscher S, Marksteiner J, Patsch JR, et al: Monocyte migration: a novel effect and signaling pathways of catestatin. Eur J Pharmacol. 598:104–111. 2008. View Article : Google Scholar : PubMed/NCBI
38	Feistritzer C, Mosheimer BA, Colleselli D, Wiedermann CJ and Kähler CM: Effects of the neuropeptide secretoneurin on natural killer cell migration and cytokine release. Regul Pept. 126:195–201. 2005. View Article : Google Scholar : PubMed/NCBI
39	Ferrero E, Magni E, Curnis F, Villa A, Ferrero ME and Corti A: Regulation of endothelial cell shape and barrier function by chromogranin A. Ann N Y Acad Sci. 971:355–358. 2002. View Article : Google Scholar : PubMed/NCBI
40	Wang H, Steeds J, Motomura Y, Deng Y, Verma-Gandhu M, El-Sharkawy RT, McLaughlin JT, Grencis RK and Khan WI: CD4⁺ T cell-mediated immunological control of enterochro-maffin cell hyperplasia and 5-hydroxytryptamine production in enteric infection. Gut. 56:949–957. 2007. View Article : Google Scholar : PubMed/NCBI
41	Cloëz-Tayarani I and Changeux JP: Nicotine and serotonin in immune regulation and inflammatory processes: a perspective. J Leukoc Biol. 81:599–606. 2007. View Article : Google Scholar
42	Stefulj J, Cicin-Sain L, Schauenstein K and Jernej B: Serotonin and immune response: effect of the amine on in vitro proliferation of rat lymphocytes. Neuroimmunomodulation. 9:103–108. 2001. View Article : Google Scholar : PubMed/NCBI
43	Betten A, Dahlgren C, Hermodsson S and Hellstrand K: Serotonin protects NK cells against oxidatively induced functional inhibition and apoptosis. J Leukoc Biol. 70:65–72. 2001.PubMed/NCBI
44	Laberge S, Cruikshank WW, Beer DJ and Center DM: Secretion of IL-16 (lymphocyte chemoattractant factor) from serotonin-stimulated CD8⁺ T cells in vitro. J Immunol. 156:310–315. 1996.PubMed/NCBI
45	Soga F, Katoh N, Inoue T and Kishimoto S: Serotonin activates human monocytes and prevents apoptosis. J Invest Dermatol. 127:1947–1955. 2007. View Article : Google Scholar : PubMed/NCBI