Modulation of interferon activity-associated soluble molecules by appendicitis and appendectomy limits colitis-identification of novel anti-colitic targets
Cheluvappa, R and Eri, R and Luo, AS and Grimm, MC, Modulation of interferon activity-associated soluble molecules by appendicitis and appendectomy limits colitis-identification of novel anti-colitic targets, Journal of Interferon and Cytokine Research, 35, (2) pp. 108-115. ISSN 1079-9907 (2015) [Refereed Article]
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.