T helper type 17 pathway suppression by appendicitis and appendectomy protects against colitis

摘要

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.