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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.

SUBMITTER: Cheluvappa R

PROVIDER: S-EPMC4312794 | biostudies-literature | 2015 Feb

REPOSITORIES: biostudies-literature

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

Cheluvappa Rajkumar R Eri Rajaraman R Luo Annie S AS Grimm Michael C MC

Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research 20140922 2

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 ...[more]

PMID: 25243802

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Project description:The appendix contains abundant lymphoid tissue and is constantly exposed to gut flora. When completed at a young age, appendicitis followed by appendectomy (AA) prevents or significantly ameliorates Inflammatory Bowel Diseases (IBDs) in later life. Inflammatory bowel disease comprises Crohn's disease and ulcerative colitis. Our murine AA model is the only existing experimental model of AA. In our unique model, AA performed in the most proximal colon limits colitis pathology in the most distal colon by curbing T-helper 17 cell activity, diminishing autophagy, modulating interferon activity-associated molecules, and suppressing endothelin vaso-activity-mediated immunopathology. In the research presented in this paper, we have examined the role of chemokines in colitis pathology with our murine AA model. Chemokines are a family of small cytokines with four conserved cysteine residues. Chemokines induce chemotaxis in adjacent cells with corresponding receptors. All 40 known chemokine genes and 24 chemokine receptor genes were examined for gene expression levels in distal colons three days post-AA and 28 days post-AA. At 28 days post-AA, the chemokine gene CCL5 was significantly upregulated. Furthermore, Gene Set Enrichment Analysis (GSEA) showed upregulation of seven CCL5-associated gene-sets 28 days post-AA in contrast to just one gene-set downregulated at the same time-point. The chemokine gene CXCL11 was significantly upregulated three days post-AA and 28 days post-AA. Evaluation using GSEA showed upregulation of six CXCL11-associated gene sets but no downregulation of any gene set. At 28 days post-AA, CCL17 gene expression was significantly downregulated. There was no expression of any chemokine receptor gene three days post-AA, but CCR10 was the only chemokine receptor gene that displayed differential gene expression (upregulation) 28 days post-AA. No CCR10-associated gene set was upregulated in GSEA in contrast to one downregulated gene set. Our analysis resulted in identifying three new therapeutic targets towards ameliorating colitis: CCL5, CXCL11, and CCL17. While CCL5 and CXCL11 are good therapeutic chemokine candidates to be exogenously administered, CCL17 is a good candidate chemokine to competitively inhibit or limit colitis pathology.

Project description:BACKGROUND: Appendicitis followed by appendectomy (AA) at a young age protects against later inflammatory bowel disease (IBD). Using a novel murine appendicitis model we earlier demonstrated that AA proffered significant protection against subsequent experimental colitis. AIM: To delineate genes and biological pathways involved in the protective effect of AA against subsequent colitis using gene set enrichment analysis (GSEA) of DNA microarray data. METHODS: Appendicitis and appendicectomy was done (5 week old male BALB/c mice) near the most proximal colon (caecal lymphoid follicles) and colonic samples were harvested from the most distal colon. Two consecutive laparotomies were done in control Sham-Sham (SS) mice. RNA was extracted (TRIzol®) from 4 individual colonic samples per group (AA group vs. SS group) with each sample taken independently through Affymetrix® microarray hybridization. For GSEA, data for more than 23,000 genes were exported from Partek and analyzed with GSEA software (with 2852 gene sets encoded) to establish correlates with phenotypes of the gene sets. RESULTS: Distal colonic expression of 636 gene-sets were significantly upregulated in AA group samples (False Discovery Rates (FDR) values < 1 % and p value < 0.001; stringent statistical selection). These were validated by quantitative PCR of 14 selected genes across the immunological spectrum and over time-intervals of 3 days, 14 days and 28 days. CONCLUSIONS: Many key immunological, apoptosis-related and cellular function-associated gene-sets involved in the protective effect of AA in experimental colitis were identified. Further analysis of these profiles and biological pathways will assist utilizing these gene products and manipulating various aspects of these pathways to develop better therapeutic strategies in the management of intractable IBD. Appendicitis and appendicectomy was done (5 week old male BALB/c mice) near the most proximal colon (caecal lymphoid follicles) and colonic samples were harvested from the most distal colon. Two consecutive laparotomies were done in control Sham-Sham (SS) mice. RNA was extracted (TRIzol®) from 4 individual colonic samples per group (AA group vs. SS group) with each sample taken independently through Affymetrix® microarray hybridization. variable_protocol: appendicitis and appendectomy: AA1, AA2, AA3, AA4 variable_protocol: sham/sham surgery: SS1, SS2, SS3, SS4 repeat_biological replicate: AA1, AA2, AA3, AA4 repeat_biological replicate: SS1, SS2, SS3, SS4 Upregulated gene-set linked as supplementary file.

Project description:BackgroundAcute appendicitis (AA) is one of the most prevalent acute abdominal diseases and appendectomy is the definitive treatment of appendicitis. However, whether appendicitis and appendectomy cause colorectal cancer (CRC) is controversial. The results of observational studies are contradictory, but randomized controlled trials (RCT) cannot be conducted.MethodsData of appendectomy, AA, and CRC were obtained from the IEU Open GWAS project. We selected several Genome-wide association studies (GWAS) summary statistics for CRC: statistics for colon cancer (CC) were obtained from MRC-IEU and Neale lab, respectively; statistics for rectum cancer (RC) were obtained from MRC-IEU and FinnGen, respectively; statistics for CRC were provided by Sakaue S et al. Mendelian randomization (MR) was used to evaluate the causal relationships between exposure and outcomes. Inverse variance weighting (IVW) was the most important analysis method. Meta-analysis was used to summarize the results of IVW to increase the reliability and sensitivity analysis was used to evaluate the robustness of the results.ResultsAccording to the results of IVW, appendectomy did not increase risk of CC: MRC-IEU (OR:1.009, 95%CI:0.984-1.035, P=0.494), Neale lab (OR:1.016, 95%CI:0.993-1.040, P=0.174); Appendectomy also did not increase risk of RC: MRC-IEU(OR:0.994, 95%CI:0.974-1.014, P=0.538), FinnGen(OR:2.791, 95%CI:0.013-580.763, P=0.706); Appendectomy also did not increase risk of CRC: Sakaue S(OR:1.382, 95%CI:0.301-6.352, P=0.678). Appendicitis did not increase risk of CC: MRC-IEU(OR:1.000, 95%CI:0.999-1.001, P=0.641), Neale lab(OR:1.000, 95%CI:1.000-1.001, P=0.319); Appendicitis also did not increase risk of RC: MRC-IEU(OR:1.000, 95%CI:0.999-1.000, P=0.361), FinnGen(OR:0.903, 95%CI:0.737-1.105, P=0.321); Appendicitis also did not increase risk of CRC: Sakaue S (OR:1.018, 95%CI:0.950-1.091, P=0.609). The results of Meta-analysis also showed appendectomy (P=0.459) and appendicitis (P=0.999) did not increase the risk of CRC.ConclusionsAppendectomy and appendicitis do not increase the risk of colorectal cancer. More clinical trials are needed in the future to verify the causal relationships.

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

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

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