title: T helper type 17 pathway suppression by appendicitis and appendectomy protects against colitis.
abstract: Appendicitis followed by appendectomy (AA) at a young age protects against inflammatory bowel disease (IBD). We wanted to characterize the role of the T helper type 17 (Th17) system involved in this protective effect. AA was performed on 5-week-old male BALB/c mice and distal-colon samples were harvested. Mice with two laparotomies each served as sham-sham (SS) controls. RNA was extracted from four individual colonic samples per group (AA and SS groups) and each sample microarray-analysed and reverse transcription-polymerase chain reaction (RT-PCR)-validated. Gene-set enrichment analysis (GSEA) showed that the Th17 recruitment factor gene CCL20 was significantly suppressed at both 3 days post-AA and 28 days post-AA. Although Th17 cell development differentiation factor genes TGF-β2 and TGF-β3 were significantly up-regulated 3 days post-AA, GSEA 28 days post-AA showed that AA down-regulated 29 gene-sets associated with TGF-β1, TGF-β2 and TGF-β3 in contrast to none up-regulated with any of these genes. GSEA showed substantial down-regulation of gene-sets associated with Th17 lymphocyte recruitment, differentiation, activation and cytokine expression in the AA group 28 days post-AA. We conclude that Th17-system cytokines are kept under control by AA via down-regulation of proinflammatory CCL20, a rapid down-regulation of pro-Th17 cell differentiation genes TGF-β2 and TGF-β3, suppression of RORC-associated gene-sets, increased protective STAT1 expression and suppression of 81 'pro-Th17' system gene-sets. AA suppresses the Th17 pathway leading to colitis amelioration. Further characterization of Th17-associated genes and biological pathways will assist in the development of better therapeutic approaches in IBD management.
authors.affiliation: Department of Medicine, St George Clinical School, University of New South Wales, Sydney, NSW, Australia.
authors.forename: R
authors.initials: R
authors.lastname: Cheluvappa
authors.forename: A S
authors.initials: AS
authors.lastname: Luo
authors.forename: M C
authors.initials: MC
authors.lastname: Grimm
mesh_terms: D000818:Animals; D001062:Appendectomy; D001064:Appendicitis / Q000276:immunology / Q000378:metabolism / Q000601:surgery*; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D054418:Chemokine CCL20 / Q000378:metabolism; D003092:Colitis / Q000517:prevention & control* / Q000601:surgery; D003106:Colon / Q000276:immunology; D015536:Down-Regulation; D015870:Gene Expression; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D050794:STAT1 Transcription Factor / Q000378:metabolism; D058504:Th17 Cells / Q000276:immunology / Q000378:metabolism*; D053781:Transforming Growth Factor beta2 / Q000378:metabolism; D053782:Transforming Growth Factor beta3 / Q000378:metabolism; D015854:Up-Regulation
chemical_list: C493447:CCL20 protein, mouse; D054418:Chemokine CCL20; D050794:STAT1 Transcription Factor; C494080:Stat1 protein, mouse; D053781:Transforming Growth Factor beta2; D053782:Transforming Growth Factor beta3
keywords: Th17 cells; appendectomy; appendicitis; colitis