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Modulation of interferon activity-associated soluble molecules by appendicitis and appendectomy limits colitis-identification of novel anti-colitic targets

journal contribution
posted on 2023-05-18, 04:34 authored by Cheluvappa, R, Rajaraman Eri, Luo, AS, Grimm, MC
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.

History

Publication title

Journal of Interferon and Cytokine Research

Volume

35

Pagination

108-115

ISSN

1079-9907

Department/School

School of Health Sciences

Publisher

Mary Ann Liebert Inc Publ

Place of publication

2 Madison Avenue, Larchmont, USA, Ny, 10538

Rights statement

Copyright 2015 Mary Ann Liebert, Inc.

Repository Status

  • Restricted

Socio-economic Objectives

Clinical health not elsewhere classified

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