Inhibition of the interleukin‑23/interleukin‑17 pathway by anti‑interleukin‑23p19 monoclonal antibody attenuates 2,4,6‑trinitrobenzene sulfonic acid‑induced Crohn's disease in rats

Yao,Jia  Yin; Lu,Yi; Zhi,Min; Li,Chu  Jun; Hu,Pin  Jin; Gao,Xiang

doi:10.3892/mmr.2014.2427

Inhibition of the interleukin‑23/interleukin‑17 pathway by anti‑interleukin‑23p19 monoclonal antibody attenuates 2,4,6‑trinitrobenzene sulfonic acid‑induced Crohn's disease in rats

Authors:
- Jia Yin Yao
- Yi Lu
- Min Zhi
- Chu Jun Li
- Pin Jin Hu
- Xiang Gao
View Affiliations

Affiliations: Department of Gastroenterology, The Sixth Affiliated Hospital of Sun Yat‑Sen University, Guangzhou, Guangdong 510655, P.R. China, Department of Anesthesiology, Guangzhou Hospital of Traditional Chinese Medicine, Guangzhou, Guangdong 510130, P.R. China
Published online on: July 28, 2014 https://doi.org/10.3892/mmr.2014.2427
Pages: 2105-2110

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 interleukin (IL)‑23/IL‑17 pathway is considered to be important in the pathogenesis of Crohn's disease (CD). The present study aimed to evaluate the effects of targeting the IL‑23/IL‑17 pathway using the anti‑IL‑23p19 monoclonal antibody (mAb) on 2,4,6‑trinitrobenzene sulfonic acid (TNBS)‑induced CD rats. A total of 60 Sprague‑Dawley rats were randomly divided into a control group, model group and an anti‑IL‑23p19 mAb treatment group (administered intramuscularly every week at a dose of 1 ml/mg). Disease activity index (DAI), colon macroscopic damage index (CMDI) and tissue damage index (TDI) were then evaluated. The mRNA expression of IL‑23p19, p40 (IL‑23/12), retinoic acid‑related orphan receptor‑γt (ROR‑γt) and IL‑17 in colonic tissues were detected by reverse transcription‑polymerase chain reaction and levels of serum IL‑23p19, p40, ROR‑γt and IL‑17 were measured using an enzyme‑linked immunosorbent assay. Anti‑IL‑23p19 mAb was found to effectively attenuate colonic inflammation demonstrated by reduced DAI, CMDI and TDI scores, improvement in pathological evaluation and downregulation of expression levels of IL‑23p19, p40 (IL‑23/12), ROR‑γt and the downstream proinflammatory cytokine, IL‑17. Anti‑IL‑23p19 mAb attenuated TNBS‑induced CD in model rats. The possible underlying mechanisms may be associated with inhibition of the IL‑23/IL‑17 pathway by inhibiting the expression of IL‑23p19 and downregulating the downstream proinflammatory cytokine IL‑17. Targeting the IL‑23/IL‑17 pathway may be a relevant and realistic therapeutic approach for the development of additive and alternative treatments to the biologics currently available in the treatment of CD.

View Figures

View References

1	Geremia A, Biancheri P, Allan P, Corazza GR and Di Sabatino A: Innate and adaptive immunity in inflammatory bowel disease. Autoimmun Rev. 13:3–10. 2013. View Article : Google Scholar
2	Oppmann B, Lesley R, Blom B, et al: Novel p19 protein engages IL-12p40 to form a cytokine, IL-23, with biological activities similar as well as distinct from IL-12. Immunity. 13:715–725. 2000. View Article : Google Scholar
3	Cua DJ, Sherlock J, Chen Y, et al: Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain. Nature. 421:744–748. 2003. View Article : Google Scholar : PubMed/NCBI
4	Vignali DA and Kuchroo VK: IL-12 family cytokines: immunological playmakers. Nat Immunol. 13:722–728. 2012. View Article : Google Scholar : PubMed/NCBI
5	Duvallet E, Semerano L, Assier E, Falgarone G and Boissier MC: Interleukin-23: a key cytokine in inflammatory diseases. Ann Med. 43:503–511. 2011. View Article : Google Scholar : PubMed/NCBI
6	Duerr RH, Taylor KD, Brant SR, et al: A genome-wide association study identifies IL23R as an inflammatory bowel disease gene. Science. 314:1461–1463. 2006. View Article : Google Scholar : PubMed/NCBI
7	McGeachy MJ, Chen Y, Tato CM, et al: The interleukin 23 receptor is essential for the terminal differentiation of interleukin 17-producing effector T helper cells in vivo. Nat Immunol. 10:314–324. 2009. View Article : Google Scholar : PubMed/NCBI
8	Rovedatti L, Kudo T, Biancheri P, et al: Differential regulation of interleukin 17 and interferon gamma production in inflammatory bowel disease. Gut. 58:1629–1636. 2009. View Article : Google Scholar : PubMed/NCBI
9	Sarra M, Pallone F, Macdonald TT and Monteleone G: IL-23/IL-17 axis in IBD. Inflamm Bowel Dis. 16:1808–1813. 2010. View Article : Google Scholar : PubMed/NCBI
10	Siakavellas SI and Bamias G: Role of the IL-23/IL-17 axis in Crohn’s disease. Discov Med. 14:253–262. 2012.
11	Toussirot E: The IL23/Th17 pathway as a therapeutic target in chronic inflammatory diseases. Inflamm Allergy Drug Targets. 1:159–168. 2012. View Article : Google Scholar : PubMed/NCBI
12	Imaeda H, Takahashi K, Fujimoto T, et al: Clinical utility of newly developed immunoassays for serum concentrations of adalimumab and anti-adalimumab antibodies in patients with Crohn’s disease. J Gastroenterol. 49:100–109. 2014.PubMed/NCBI
13	Peyrin-Biroulet L and Danese S: Stopping infliximab in Crohn’s disease: still an ongoing STORI. Inflamm Bowel Dis. 18:2201–2202. 2012.
14	Kilkenny C, Browne WJ, Cuthill IC, Emerson M and Altman DG: Improving bioscience research reporting: the ARRIVE guidelines for reporting animal research. PLoS Biol. 8:e10004122010. View Article : Google Scholar : PubMed/NCBI
15	Morris GP, Beck PL, Herridge MS, et al: Hapten-induced model of chronic inflammation and ulceration in the rat colon. Gastroenterology. 96:795–803. 1989.PubMed/NCBI
16	Murthy SN, Cooper HS, Shim H, Shah RS, Ibrahim SA and Sedergran DJ: Treatment of dextran sulfate sodium-induced murine colitis by intracolonic cyclosporin. Dig Dis Sci. 38:1722–1734. 1993. View Article : Google Scholar : PubMed/NCBI
17	Murano M, Maemura K, Hirata I, et al: Therapeutic effect of intracolonically administered nuclear factor kappa B (p65) antisense oligonucleotide on mouse dextran sulphate sodium (DSS)-induced colitis. Clin Exp Immunol. 120:51–58. 2000. View Article : Google Scholar
18	Wallace JL and Keenan CM: An orally active inhibitor of leukotriene synthesis accelerates healing in a rat model of colitis. Am J Physiol. 258:G527–G534. 1990.PubMed/NCBI
19	Guo L, Ye C, Hao X, et al: Carboxyamidotriazole ameliorates experimental colitis by inhibition of cytokine production, nuclear factor-κB activation, and colonic fibrosis. J Pharmacol Exp Ther. 342:356–365. 2012.PubMed/NCBI
20	Zingarelli B, Hake PW, Burroughs TJ, Piraino G, O’Connor M and Denenberg A: Activator protein-1 signalling pathway and apoptosis are modulated by poly(ADP-ribose) polymerase-1 in experimental colitis. Immunology. 113:509–517. 2004. View Article : Google Scholar : PubMed/NCBI
21	Neurath MF, Fuss I, Kelsall BL, Stüber E and Strober W: Antibodies to interleukin 12 abrogate established experimental colitis in mice. J Exp Med. 182:1281–1290. 1995. View Article : Google Scholar : PubMed/NCBI
22	Strober W, Lúdvíksson BR and Fuss IJ: The pathogenesis of mucosal inflammation in murine models of inflammatory bowel disease and Crohn disease. Ann Intern Med. 128:848–856. 1998. View Article : Google Scholar : PubMed/NCBI
23	Torres MI, Garcia-Martin M, Fernandez MI, Nieto N, Gil A and Rios A: Experimental colitis induced by trinitrobenzenesulfonic acid: an ultrastructural and histochemical study. Dig Dis Sci. 44:2523–2529. 1999. View Article : Google Scholar : PubMed/NCBI
24	Lakatos PL and Lakatos L: Ulcerative proctitis: a review of pharmacotherapy and management. Expert Opin Pharmacother. 9:741–749. 2008. View Article : Google Scholar : PubMed/NCBI
25	Burger D and Travis S: Conventional medical management of inflammatory bowel disease. Gastroenterology. 140:1827–1837. 2011. View Article : Google Scholar : PubMed/NCBI
26	Magro F and Portela F: Management of inflammatory bowel disease with infliximab and other anti-tumor necrosis factor alpha therapies. BioDrugs. 24:3–14. 2010. View Article : Google Scholar : PubMed/NCBI
27	Mariette X, Matucci-Cerinic M, Pavelka K, et al: Malignancies associated with tumour necrosis factor inhibitors in registries and prospective observational studies: a systematic review and meta-analysis. Ann Rheum Dis. 70:1895–1904. 2011. View Article : Google Scholar
28	Deepak P, Sifuentes H, Sherid M, Stobaugh D, Sadozai Y and Ehrenpreis ED: T-cell non-Hodgkin’s lymphomas reported to the FDA AERS with tumor necrosis factor-alpha (TNF-α) inhibitors: results of the REFURBISH study. Am J Gastroenterol. 108:99–105. 2013.
29	Huang R, Valerian BT and Lee EC: Laparoscopic approach in patients with recurrent Crohn’s disease. Am Surg. 78:595–599. 2012.
30	Ivanov II, McKenzie BS, Zhou L, et al: The orphan nuclear receptor RORgammat directs the differentiation program of proinflammatory IL-17⁺ T helper cells. Cell. 126:1121–1133. 2006. View Article : Google Scholar : PubMed/NCBI
31	Ono Y, Kanai T, Sujino T, et al: T-helper 17 and interleukin-17-producing lymphoid tissue inducer-like cells make different contributions to colitis in mice. Gastroenterology. 143:1288–1297. 2012. View Article : Google Scholar : PubMed/NCBI
32	Guan Q, Ma Y, Hillman CL, et al: Targeting IL-12/IL-23 by employing a p40 peptide-based vaccine ameliorates TNBS-induced acute and chronic murine colitis. Mol Med. 17:646–656. 2011. View Article : Google Scholar : PubMed/NCBI
33	De Nitto D, Sarra M, Cupi ML, Pallone F and Monteleone G: Targeting IL-23 and Th17-cytokines in inflammatory bowel diseases. Curr Pharm Des. 16:3656–3660. 2010.PubMed/NCBI
34	Monteleone I, Pallone F and Monteleone G: Interleukin-23 and Th17 cells in the control of gut inflammation. Mediators Inflamm. 2009:2976452009. View Article : Google Scholar : PubMed/NCBI
35	Cho JH and Brant SR: Recent insights into the genetics of inflammatory bowel disease. Gastroenterology. 140:1704–1712. 2011. View Article : Google Scholar : PubMed/NCBI
36	Kurzeja M, Rudnicka L and Olszewska M: New interleukin-23 pathway inhibitors in dermatology: ustekinumab, briakinumab and secukinumab. Am J Clin Dermatol. 12:113–125. 2011. View Article : Google Scholar : PubMed/NCBI
37	Tzellos T, Kyrgidis A, Trigoni A and Zouboulis CC: Association of ustekinumab and briakinumab with major adverse cardiovascular events: An appraisal of meta-analyses and industry sponsored pooled analyses to date. Dermatoendocrinol. 4:320–323. 2012. View Article : Google Scholar