title: Modulation of interferon activity-associated soluble molecules by appendicitis and appendectomy limits colitis-identification of novel anti-colitic targets.
abstract: The therapeutic efficacy of interferons (IFNs) in ulcerative colitis is minimal. However, IFN activity-associated molecules have been inadequately investigated. Appendicitis and appendectomy (AA), when done while young, protect against colitis development later. Our novel murine AA model protects against colitis. This therapeutic target-identifying study enumerates IFN activity-associated molecules involved in this protection. Mice with 2 laparotomies were controls (sham-sham/SS). Distal colons were harvested (4 AA-group colons and 4 SS-group colons). Microarray-analysis/reverse transcriptase-polymerase chain reaction-validation was done from RNA from each (3-days/28-days-post-AA). Gene set enrichment analysis (GSEA) software was used to analyze distal colonic gene sets associated with 46 IFN activity-related genes. More AA-upregulated gene sets were associated with IFIT1, IFIT2, IFIT3, IRF7, IFI35, and IFI44 (False Discovery Rate-FDR <5% and P<0.001), although only IFIT1, IFIT2, IFIT3, and IFI44 showed individual gene upregulation (P<0.05). More AA-downregulated gene sets were associated with IRF1, IRF2, IRF4, IRF8, IRF9, IRF2BP1, IFRD1, IFRD2, and IFIH1 (FDR <5%/P<0.001); although only IRF2BP1 showed individual gene downregulation (P<0.05). There was significant upregulation (P<0.05) of IFNZ; and downregulation of IRF2BP2 and IFI30, despite no major associated GSEA differences. IFIT1, IFIT2, IFIT3, and IFI44, with profound AA-induced individual/GSEA upregulation, and their immunomodulatory/ antiproliferative activity, are the best molecules to investigate therapeutic potential. IRF4, IRF8, IRF2BP1, IFRD1, and IFRD2, owing to their profound AA-induced gene set downregulation, and because of their diverse lymphocytic activity, are good targets to competitively inhibit or to treat with exogenous products in knockout animals.
authors.affiliation: 1 Department of Medicine, St. George Clinical School, University of New South Wales , Sydney, Australia .
authors.forename: Rajkumar
authors.initials: R
authors.lastname: Cheluvappa
authors.forename: Rajaraman
authors.initials: R
authors.lastname: Eri
authors.forename: Annie S
authors.initials: AS
authors.lastname: Luo
authors.forename: Michael C
authors.initials: MC
authors.lastname: Grimm
mesh_terms: D000818:Animals; D001062:Appendectomy; D001064:Appendicitis / Q000276:immunology / Q000473:pathology / Q000601:surgery; D002352:Carrier Proteins / Q000276:immunology; D003092:Colitis / Q000276:immunology / Q000473:pathology / Q000628:therapy; D005786:Gene Expression Regulation / Q000276:immunology*; D050835:Interferon Regulatory Factors / Q000276:immunology*; D007372:Interferons / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C
chemical_list: D002352:Carrier Proteins; D050835:Interferon Regulatory Factors; D007372:Interferons