Genetic deletion of IL-25 (IL-17E) confers resistance to dextran sulfate sodium-induced colitis in mice

Cell & Bioscience

Aiping Zhao²  Zhonghan Yang¹  Terez Shea-Donohue²  Nonghua Lu³  Thomas A Wynn⁵  Thirumalai R Ramalingam⁵  Joseph F Urban⁴  Yanfei Li²  Allen Smith⁴  An-Jiang Wang³ 

[1] Department of Biochemistry, Zhongshan Medical School, Sun Yat-sen University, 74 Zhongshan 2nd Road, Guangzhou 510080, China;Departments of Radiation Oncology and Medicine, University of Maryland School of Medicine, 10 S. Pine Street, MSTF, Room 7-00D, Baltimore, MD 21201, USA;Department of Gastroenterology and Hepatology, The First Affiliated Hospital of Nanchang University, Nanchang 330006, China;U.S. Department of Agriculture, Beltsville Human Nutrition Research Center, Agricultural Research Service, Diet, Genomics, and Immunology Laboratory, Beltsville, MD 20705, USA;Immunopathogenesis Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA

关键词: IL-33;    IL-13;    Mice;    DSS;    Colitis;    IL-25;   

Others  :  1135314
DOI  :  10.1186/2045-3701-4-72

 received in 2014-08-26, accepted in 2014-11-17,  发布年份 2014

【 摘 要 】

Background

IL-25 is emerging as a key regulator of inflammation in the intestinal mucosa because of its ability to promote type 2 while suppressing Th1 and Th17 responses. Several previous studies reported inconsistent results on the role of exogenous IL-25 in development of colonic inflammation and none were performed in animals with a genetic deletion of IL-25. We investigated the contribution of endogenous IL-25 to DSS-induced colitis using mice deficient in IL-25.

Results

Mice were exposed to DSS in drinking water ad libitum either for seven days (acute) or for three cycles of seven days with DSS followed by 14 days without DSS (chronic) to induce colitis, respectively. The loss of body weight, appearance of diarrhea and bloody stools, and shortening of colon length were significantly less pronounced in IL-25^−/− mice compared to WT mice after exposure to acute DSS. Histological examination showed that DSS-treated IL-25^−/− mice had only mild inflammation in the colon, while severe inflammation developed in DSS-treated WT mice. A significant up-regulation of IL-33 was observed in acute DSS-treated WT but not in the IL-25^−/− mice. There was significantly lower expression of pro-inflammatory cytokines in the colon of acute DSS-treated IL-25^−/− compared to WT mice. IL-25^−/− mice were also partially protected from chronic DSS challenge especially during the first 2 cycles of DSS exposure. In contrast to IL-25^−/− mice, IL-13^−/− mice were more susceptible to DSS-induced colitis. Finally, stimulation of T84 colonic epithelial cells with IL-25 up-regulated the expression of IL-33 and several pro-inflammatory cytokines.

Conclusions

These data indicate that endogenous IL-25 acts as a pro-inflammatory factor in DSS-induced colitis, which is unlikely to be mediated by IL-13 but possibly the induction of IL-33 and other pro-inflammatory mediators from colonic epithelial cells. The present study suggests that IL-25 may contribute to the pathogenesis of inflammatory bowel disease in at least a subgroup of patients.

【 授权许可】

   
2014 Wang et al.; licensee BioMed Central Ltd.

【 图 表 】

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【 参考文献 】

• [1]Hanauer SB: Inflammatory bowel disease: epidemiology, pathogenesis, and therapeutic opportunities. Inflamm Bowel Dis 2006, 12(Suppl):S3-S9.
• [2]Targan SR: Current limitations of IBD treatment: where do we go from here? Ann N Y Acad Sci 2006, 1072:1-8.
• [3]Bamias G, Cominelli F: Immunopathogenesis of inflammatory bowel disease: current concepts. Curr Opin Gastroenterol 2007, 23:365-369.
• [4]Cobrin GM, Abreu MT: Defects in mucosal immunity leading to Crohn's disease. Immunol Rev 2005, 206:277-295.
• [5]Pizarro TT, Cominelli F: Cytokine therapy for Crohn's disease: advances in translational research. Annu Rev Med 2007, 58:433-444.
• [6]Fuss IJ, Heller F, Boirivant M, Leon F, Yoshida M, Fichtner-Feigl S, Yang Z, Exley M, Kitani A, Blumberg RS, Mannon P, Strober W: Nonclassical CD1d-restricted NK T cells that produce IL-13 characterize an atypical Th2 response in ulcerative colitis. J Clin Invest 2004, 113:1490-1497.
• [7]Heller F, Florian P, Bojarski C, Richter J, Christ M, Hillenbrand B, Mankertz J, Gitter AH, Burgel N, Fromm M, Zeitz M, Fuss I, Strober W, Schulzke JD: Interleukin-13 is the key effector Th2 cytokine in ulcerative colitis that affects epithelial tight junctions, apoptosis, and cell restitution. Gastroenterology 2005, 129:550-564.
• [8]Fuss IJ, Neurath M, Boirivant M, Klein JS, de la Motte C, Strong SA, Fiocchi C, Strober W: Disparate CD4+ lamina propria (LP) lymphokine secretion profiles in inflammatory bowel disease. Crohn's disease LP cells manifest increased secretion of IFN-gamma, whereas ulcerative colitis LP cells manifest increased secretion of IL-5. J Immunol 1996, 157:1261-1270.
• [9]Schmidt C, Giese T, Ludwig B, Mueller-Molaian I, Marth T, Zeuzem S, Meuer SC, Stallmach A: Expression of interleukin-12-related cytokine transcripts in inflammatory bowel disease: elevated interleukin-23p19 and interleukin-27p28 in Crohn's disease but not in ulcerative colitis. Inflamm Bowel Dis 2005, 11:16-23.
• [10]Fujino S, Andoh A, Bamba S, Ogawa A, Hata K, Araki Y, Bamba T, Fujiyama Y: Increased expression of interleukin 17 in inflammatory bowel disease. Gut 2003, 52:65-70.
• [11]Nielsen OH, Kirman I, Rudiger N, Hendel J, Vainer B: Upregulation of interleukin-12 and −17 in active inflammatory bowel disease. Scand J Gastroenterol 2003, 38:180-185.
• [12]Zhang Z, Zheng M, Bindas J, Schwarzenberger P, Kolls JK: Critical role of IL-17 receptor signaling in acute TNBS-induced colitis. Inflamm Bowel Dis 2006, 12:382-388.
• [13]Owyang AM, Zaph C, Wilson EH, Guild KJ, McClanahan T, Miller HR, Cua DJ, Goldschmidt M, Hunter CA, Kastelein RA, Artis D: Interleukin 25 regulates type 2 cytokine-dependent immunity and limits chronic inflammation in the gastrointestinal tract. J Exp Med 2006, 203:843-849.
• [14]Kleinschek MA, Owyang AM, Joyce-Shaikh B, Langrish CL, Chen Y, Gorman DM, Blumenschein WM, McClanahan T, Brombacher F, Hurst SD, Kastelein RA, Cua DJ: IL-25 regulates Th17 function in autoimmune inflammation. J Exp Med 2007, 204:161-170.
• [15]Zaph C, Du Y, Saenz SA, Nair MG, Perrigoue JG, Taylor BC, Troy AE, Kobuley DE, Kastelein RA, Cua DJ, Yu Y, Artis D: Commensal-dependent expression of IL-25 regulates the IL-23-IL-17 axis in the intestine. J Exp Med 2008, 205:2191-2198.
• [16]Caruso R, Sarra M, Stolfi C, Rizzo A, Fina D, Fantini MC, Pallone F, MacDonald TT, Monteleone G: Interleukin-25 inhibits interleukin-12 production and Th1 cell-driven inflammation in the Gut. Gastroenterology 2009, 136:2270-2279.
• [17]Camelo A, Barlow J, Drynan L, Neill D, Ballantyne S, Wong S, Pannell R, Gao W, Wrigley K, Sprenkle J, McKenzie A: Blocking IL-25 signalling protects against gut inflammation in a type-2 model of colitis by suppressing nuocyte and NKT derived IL-13. J Gastroenterol 2012, 47:1198-1211.
• [18]Monteleone G, Pallone F, MacDonald TT: Interleukin-25: a two-edged sword in the control of immune-inflammatory responses. Cytokine Growth Factor Rev 2010, 21:471-475.
• [19]Mchenga SSS, Wang D, Li C, Shan F, Lu C: Inhibitory effect of recombinant IL-25 on the development of dextran sulfate sodium-induced experimental colitis in mice. Cell Mol Immunol 2008, 5:425-431.
• [20]Salum Mchenga SS, Wang D, Janneh FM, Feng Y, Zhang P, Li Z, Lu C: Differential dose effects of recombinant IL-25 on the development of dextran sulfate sodium-induced colitis. Inflamm Res 2010, 59:879-887.
• [21]Pushparaj PN, Li D, Komai-Koma M, Guabiraba R, Alexander J, McSharry C, Xu D: Interleukin-33 exacerbates acute colitis via interleukin-4 in mice. Immunology 2013, 140:70-77.
• [22]Sedhom MA, Pichery M, Murdoch JR, Foligne B, Ortega N, Normand S, Mertz K, Sanmugalingam D, Brault L, Grandjean T, Lefrancais E, Fallon PG, Quesniaux V, Peyrin-Biroulet L, Cathomas G, Junt T, Chamaillard M, Girard JP, Ryffel B: Neutralisation of the interleukin-33/ST2 pathway ameliorates experimental colitis through enhancement of mucosal healing in mice. Gut 2013, 62:1714-1723.
• [23]Fallon PG, Ballantyne SJ, Mangan NE, Barlow JL, Dasvarma A, Hewett DR, McIlgorm A, Jolin HE, McKenzie AN: Identification of an interleukin (IL)-25-dependent cell population that provides IL-4, IL-5, and IL-13 at the onset of helminth expulsion. J Exp Med 2006, 203:1105-1116.
• [24]Kang Z, Swaidani S, Yin W, Wang C, Barlow J, Gulen M, Bulek K, Do J, Aronica M, McKenzie A, Min B, Li X: Epithelial cell-specific Act1 adaptor mediates interleukin-25-dependent helminth expulsion through expansion of Lin(−)c-Kit(+) innate cell population. Immunity 2012, 36:821-833.
• [25]Fort MM, Cheung J, Yen D, Li J, Zurawski SM, Lo S, Menon S, Clifford T, Hunte B, Lesley R, Muchamuel T, Hurst SD, Zurawski G, Leach MW, Gorman DM, Rennick DM: IL-25 induces IL-4, IL-5, and IL-13 and Th2-associated pathologies in vivo. Immunity 2001, 15:985-995.
• [26]Zhao A, Urban JF, Sun R, Stiltz J, Morimoto M, Notari L, Madden KB, Yang Z, Grinchuk V, Ramalingam TR, Wynn TA, Shea-Donohue T: Critical role of IL-25 in nematode infection-induced alterations in intestinal function. J Immunol 2010, 185:6921-6929.
• [27]Licona-Limon P, Kim LK, Palm NW, Flavell RA: TH2, allergy and group 2 innate lymphoid cells. Nat Immunol 2013, 14:536-542.
• [28]Alex P, Zachos NC, Nguyen T, Gonzales L, Chen TE, Conklin LS, Centola M, Li X: Distinct cytokine patterns identified from multiplex profiles of murine DSS and TNBSΓÇÉInduced colitis. Inflamm Bowel Dis 2009, 15:341-352.
• [29]Pastorelli L, De Salvo C, Vecchi M, Pizarro TT: The role of IL-33 in gut mucosal inflammation. Mediators Inflamm 2013, 2013:608187.
• [30]Liew FY, Pitman NI, McInnes IB: Disease-associated functions of IL-33: the new kid in the IL-1 family. Nat Rev Immunol 2010, 10:103-110.
• [31]Schmitz J, Owyang A, Oldham E, Song Y, Murphy E, McClanahan TK, Zurawski G, Moshrefi M, Qin J, Li X, Gorman DM, Bazan JF, Kastelein RA: IL-33, an interleukin-1-like cytokine that signals via the IL-1 receptor-related protein ST2 and induces T helper type 2-associated cytokines. Immunity 2005, 23:479-490.
• [32]Salas A: The IL-33/ST2 axis: yet another therapeutic target in inflammatory bowel disease? Gut 2013, 62:1392-1393.
• [33]Beltran CJ, Nunez LE, Diaz-Jimenez D, Farfan N, Candia E, Heine C, Lopez F, Gonzalez MJ, Quera R, Hermoso MA: Characterization of the novel ST2/ILΓÇÉ33 system in patients with inflammatory bowel disease. Inflamm Bowel Dis 2010, 16:1097-1107.
• [34]Yang Z, Sun R, Grinchuk V, Blanco JAF, Notari L, Bohl JA, McLean LP, Ramalingam TR, Wynn TA, Urban JF, Vogel SN, Shea-Donohue T, Zhao A: IL-33-induced alterations in murine intestinal function and cytokine responses are MyD88, STAT6, and IL-13 dependent. Am J Physiol Gastrointest Liver Physiol 2013, 304:G381-G389.
• [35]Zhao A, McDermott J, Urban JF Jr, Gause W, Madden KB, Yeung KA, Morris SC, Finkelman FD, Shea-Donohue T: Dependence of IL-4, IL-13, and nematode-induced alterations in murine small intestinal smooth muscle contractility on Stat6 and enteric nerves. J Immunol 2003, 171:948-954.
• [36]Neurath MF: New targets for mucosal healing and therapy in inflammatory bowel diseases. Mucosal Immunol 2014, 7:6-19.
• [37]Heller F, Fuss IJ, Nieuwenhuis EE, Blumberg RS, Strober W: Oxazolone colitis, a Th2 colitis model resembling ulcerative colitis, is mediated by IL-13-producing NK-T cells. Immunity 2002, 17:629-638.
• [38]Shea-Donohue T, Fasano A, Smith A, Zhao A: Enteric pathogens and gut function: role of cytokines and STATs. Gut Microbes 2010, 1:316-324.
• [39]Elrod JW, Laroux SF, Houghton J, Carpenter A, Ando T, Jennings MH, Grisham M, Walker N, Alexander SJ: DSS-induced colitis is exacerbated in STAT-6 knockout mice. Inflamm Bowel Dis 2005, 11:883-889.
• [40]Shajib M, Wang H, Kim JJ, Sunjic I, Ghia JE, Denou E, Collins M, Denburg JA, Khan WI: Interleukin 13 and serotonin: linking the immune and endocrine systems in murine models of intestinal inflammation. PLoS ONE 2013, 8:e72774.
• [41]Kaser A, Zeissig S, Blumberg RS: Inflammatory bowel disease. Annu Rev Immunol 2010, 28:573-621.
• [42]McKenzie GJ, Bancroft A, Grencis RK, McKenzie ANJ: A distinct role for interleukin-13 in Th2-cell-mediated immune responses. Curr Biol 1998, 8:339-342.
• [43]Maxwell JR, Brown WA, Smith CL, Byrne FR, Viney JL: Methods of inducing inflammatory bowel disease in mice. Curr Protoc Pharmacol 2009, 47:5.58.1-5.58.37.
• [44]Obermeief F, Kojouharoff G, Hans W, Scholmerich J, Gross V, Falk W: Interferon-gamma (IFN-gamma)- and tumour necrosis factor (TNF)-induced nitric oxide as toxic effector molecule in chronic dextran sulphate sodium (DSS)-induced colitis in mice. Clin Exp Immunol 1999, 116:238-245.