Protective pathways against colitis mediated by appendicitis and appendectomy

R Cheluvappa

A Luo

C Palmer

M Grimm

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^{Department of Medicine, St George Clinical School, Sydney, NSW, Australia}

^{Inflammation and Infection Research Centre, School of Medical Sciences, University of New South Wales, Sydney, NSW, Australia}

R. Cheluvappa, Inflammation and Infection Research Centre, School of Medical Sciences, Wallace Wurth Building, University of New South Wales, Gate 9 High Street, Sydney, NSW 2052, Australia. E-mail: ua.ude.wsnu@appavulehc.r

Accepted 2011 May 19.

Abstract

Appendicitis followed by appendectomy (AA) at a young age protects against inflammatory bowel disease (IBD). Using a novel murine appendicitis model, we showed that AA protected against subsequent experimental colitis. To delineate genes/pathways involved in this protection, AA was performed and samples harvested from the most distal colon. RNA was extracted from four individual colonic samples per group (AA group and double-laparotomy control group) and each sample microarray analysed followed by gene-set enrichment analysis (GSEA). The gene-expression study was validated by quantitative reverse transcription–polymerase chain reaction (RT–PCR) of 14 selected genes across the immunological spectrum. Distal colonic expression of 266 gene-sets was up-regulated significantly in AA group samples (false discovery rates < 1%; P-value < 0·001). Time–course RT–PCR experiments involving the 14 genes displayed down-regulation over 28 days. The IBD-associated genes tnfsf10, SLC22A5, C3, ccr5, irgm, ptger4 and ccl20 were modulated in AA mice 3 days after surgery. Many key immunological and cellular function-associated gene-sets involved in the protective effect of AA in experimental colitis were identified. The down-regulation of 14 selected genes over 28 days after surgery indicates activation, repression or de-repression of these genes leading to downstream AA-conferred anti-colitis protection. Further analysis of these genes, profiles and biological pathways may assist in developing better therapeutic strategies in the management of intractable IBD.

Keywords: appendectomy, appendicitis, colitis, Th17 system

Abstract

The gene-set groups chosen for further evaluation had stringent cut-off values (FDR < 1% and P < 0·001). Using these criteria, there were no gene-sets up-regulated in the SS group. However, 266 gene-sets were up-regulated in the AA group. SS group: sham and sham group; AA group: appendicitis and appendectomy group; FDR: false discovery rate.

Acknowledgments

National Health and Medical Research Council (NHMRC) for funding this study. We acknowledge Warren Kaplan and Mark J Cowley from Peter Wills Bioinformatics Centre, Garvan Institute of Medical Research, Sydney, Australia who conducted the Gene Set Enrichment Analysis for us.

Acknowledgments

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