Cytokine IL‑6 is required in Citrobacter rodentium infection‑induced intestinal Th17 responses and promotes IL‑22 expression in inflammatory bowel disease

Li,Lei; Shi,Qing‑Guo; Lin,Fang; Liang,Yu‑Guang; Sun,Li‑Jian; Mu,Jin‑Song; Wang,Yong‑Gang; Su,Hai‑Bin; Xu,Biao; Ji,Cheng‑Cheng; Huang,Hui‑Huang; Li,Ke; Wang,Hui‑Fen

doi:10.3892/mmr.2014.1898

Cytokine IL‑6 is required in Citrobacter rodentium infection‑induced intestinal Th17 responses and promotes IL‑22 expression in inflammatory bowel disease

Authors:
- Lei Li
- Qing‑Guo Shi
- Fang Lin
- Yu‑Guang Liang
- Li‑Jian Sun
- Jin‑Song Mu
- Yong‑Gang Wang
- Hai‑Bin Su
- Biao Xu
- Cheng‑Cheng Ji
- Hui‑Huang Huang
- Ke Li
- Hui‑Fen Wang
View Affiliations

Affiliations: The Medical College of Chinese PLA and PLA General Hospital, Beijing 100853, P.R. China, Department of Biotechnology, Academy of Military Medical Sciences, Beijing 100071, P.R. China, Department of Intensive Care Unit, The 302 Military Hospital, Beijing 100039, P.R. China, Department of Pharmacology, Affiliated Hospital of Academy of Military Medical Sciences, Beijing 100071, P.R. China
Published online on: January 14, 2014 https://doi.org/10.3892/mmr.2014.1898
Pages: 831-836

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

Citrobacter rodentium (C. rodentium) infection is a widely used murine model to mimic human enteric bacteria infection and inflammatory bowel disease (IBD). In this model, interleukin (IL)‑17A plays critical roles in increasing chemokine and cytokine production in various tissues to recruit innate cells, including monocytes and neutrophils, to the local site of infection. However, the source of IL‑17A remains unclear, as the majority of cell types produce IL‑17A, including intestinal endothelium cells, innate immune cells and CD4+ T cells in disease development. In the current study, wild‑type B6 mice were treated with C. rodentium and the CD4+ Th17 cell subset was observed as being specifically increased in Peyer's patches (PP), but not in mesenteric draining lymph nodes. Furthermore, the research suggested that the differentiation and activation of Th17 cells in PP were dependent on the inflammatory cytokine IL‑6, as blocking IL‑6 signaling with neutralizing antibodies decreased Th17 cells and resulted in the mice being more susceptible to C. rodentium infection. These results confirmed that the Th17 cell subset was specifically activated in PP and demonstrated that IL‑6 is required in Th17 cell activation, which are important to the clinical treatment of IBD.

View Figures

View References

1	Mundy R, MacDonald TT, Dougan G, Frankel G and Wiles S: Citrobacter rodentium of mice and man. Cell Microbiol. 7:1697–1706. 2005. View Article : Google Scholar
2	Luperchio SA and Schauer DB: Molecular pathogenesis of Citrobacter rodentium and transmissible murine colonic hyperplasia. Microbes Infect. 3:333–340. 2001.
3	Borenshtein D, McBee ME and Schauer DB: Utility of the Citrobacter rodentium infection model in laboratory mice. Curr Opin Gastroenterol. 24:32–37. 2008.
4	Kim YG, Kamada N, Shaw MH, Warner N, Chen GY, Franchi L and Núñez G: The Nod2 sensor promotes intestinal pathogen eradication via the chemokine CCL2-dependent recruitment of inflammatory monocytes. Immunity. 34:769–780. 2011. View Article : Google Scholar : PubMed/NCBI
5	Johnson E and Barthold SW: The ultrastructure of transmissible murine colonic hyperplasia. Am J Pathol. 97:291–313. 1979.PubMed/NCBI
6	Morgan ET, Goralski KB, Piquette-Miller M, et al: Regulation of drug-metabolizing enzymes and transporters in infection, inflammation, and cancer. Drug Metab Dispos. 36:205–216. 2008. View Article : Google Scholar : PubMed/NCBI
7	Neurath MF, Weigmann B, Finotto S, et al: The transcription factor T-bet regulates mucosal T cell activation in experimental colitis and Crohn’s disease. J Exp Med. 195:1129–1143. 2002.PubMed/NCBI
8	Nenci A, Becker C, Wullaert A, et al: Epithelial NEMO links innate immunity to chronic intestinal inflammation. Nature. 446:557–561. 2007. View Article : Google Scholar : PubMed/NCBI
9	Gibson DL, Ma C, Bergstrom KS, Huang JT, Man C and Vallance BA: MyD88 signalling plays a critical role in host defence by controlling pathogen burden and promoting epithelial cell homeostasis during Citrobacter rodentium-induced colitis. Cell Microbiol. 10:618–631. 2008. View Article : Google Scholar : PubMed/NCBI
10	Gibson DL, Ma C, Rosenberger CM, et al: Toll-like receptor 2 plays a critical role in maintaining mucosal integrity during Citrobacter rodentium-induced colitis. Cell Microbiol. 10:388–403. 2008.PubMed/NCBI
11	Lebeis SL, Bommarius B, Parkos CA, Sherman MA and Kalman D: TLR signaling mediated by MyD88 is required for a protective innate immune response by neutrophils to Citrobacter rodentium. J Immunol. 179:566–577. 2007. View Article : Google Scholar : PubMed/NCBI
12	Eckmann L: Animal models of inflammatory bowel disease: lessons from enteric infections. Ann N Y Acad Sci. 1072:28–38. 2006. View Article : Google Scholar : PubMed/NCBI
13	Vallance BA, Deng W, Knodler LA and Finlay BB: Mice lacking T and B lymphocytes develop transient colitis and crypt hyperplasia yet suffer impaired bacterial clearance during Citrobacter rodentium infection. Infect Immun. 70:2070–2081. 2002. View Article : Google Scholar
14	Shiomi H, Masuda A, Nishiumi S, et al: Gamma interferon produced by antigen-specific CD4⁺ T cells regulates the mucosal immune responses to Citrobacter rodentium infection. Infect Immun. 78:2653–2666. 2010. View Article : Google Scholar : PubMed/NCBI
15	Bry L and Brenner MB: Critical role of T cell-dependent serum antibody, but not the gut-associated lymphoid tissue, for surviving acute mucosal infection with Citrobacter rodentium, an attaching and effacing pathogen. J Immunol. 172:433–441. 2004. View Article : Google Scholar : PubMed/NCBI
16	Sonnenberg GF, Monticelli LA, Elloso MM, Fouser LA and Artis D: CD4(+) lymphoid tissue-inducer cells promote innate immunity in the gut. Immunity. 34:122–134. 2011.
17	Ishigame H, Kakuta S, Nagai T, et al: Differential roles of interleukin-17A and -17F in host defense against mucoepithelial bacterial infection and allergic responses. Immunity. 30:108–119. 2009. View Article : Google Scholar : PubMed/NCBI
18	Ivanov II, Atarashi K, Manel N, et al: Induction of intestinal Th17 cells by segmented filamentous bacteria. Cell. 139:485–498. 2009. View Article : Google Scholar : PubMed/NCBI
19	Chiricozzi A, Guttman-Yassky E, Suarez-Fariñas M, et al: Integrative responses to IL-17 and TNF-α in human keratinocytes account for key inflammatory pathogenic circuits in psoriasis. J Invest Dermatol. 131:677–687. 2011.
20	Geddes K, Rubino SJ, Magalhaes JG, et al: Identification of an innate T helper type 17 response to intestinal bacterial pathogens. Nat Med. 17:837–844. 2011. View Article : Google Scholar : PubMed/NCBI
21	Miossec P, Korn T and Kuchroo VK: Interleukin-17 and type 17 helper T cells. N Engl J Med. 361:888–898. 2009. View Article : Google Scholar : PubMed/NCBI
22	O’Dell JR, Elliott JR, Mallek JA, et al: Treatment of early seropositive rheumatoid arthritis: doxycycline plus methotrexate versus methotrexate alone. Arthritis Rheum. 54:621–627. 2006.PubMed/NCBI
23	Sartor RB: Microbial influences in inflammatory bowel diseases. Gastroenterology. 134:577–594. 2008. View Article : Google Scholar : PubMed/NCBI
24	Buonocore S, Ahern PP, Uhlig HH, Ivanov II, Littman DR, Maloy KJ and Powrie F: Innate lymphoid cells drive interleukin-23-dependent innate intestinal pathology. Nature. 464:1371–1375. 2010. View Article : Google Scholar : PubMed/NCBI
25	Hirota K, Turner JE, Villa M, Duarte JH, Demengeot J, Steinmetz OM and Stockinger B: Plasticity of TH17 cells in Peyer’s patches is responsible for the induction of T cell-dependent IgA responses. Nat Immunol. 14:372–379. 2013.