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Toll-Interacting Protein Regulates Immune Cell Infiltration and Promotes Colitis-Associated Cancer.

ABSTRACT: Expression of Toll-interacting protein (Tollip), a potent TLR modulator, decreases in patients with inflammatory bowel diseases (IBD), whereas Tollip-/- mice are susceptible to colitis. Tollip expression was shown to be reduced in sporadic adenoma . In contrast, we found variable Tollip expression in patients with colitis-associated adenomas. In Tollip-/- mice challenged to develop colitis-associated cancer (CAC), tumor formation was significantly reduced owing to decreased mucosal proliferative and apoptotic indexes. This protection was associated with blunt inflammatory responses without significant changes in microbial composition. mRNA expression of Cd62l and Ccr5 homing receptors was reduced in colons of untreated Tollip-/- mice, whereas CD62L+ CD8+ T cells accumulated in the periphery. In Tollip-deficient adenomas Ctla-4 mRNA expression and tumor-infiltrating CD4+ Foxp3+ regulatory T cell (Treg) were decreased. Our data show that protection from CAC in Tollip-deficient mice is associated with defects in lymphocyte accumulation and composition in colitis-associated adenomas.

SUBMITTER: Begka C

PROVIDER: S-EPMC7049660 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Toll-Interacting Protein Regulates Immune Cell Infiltration and Promotes Colitis-Associated Cancer.

Begka Christina C Pattaroni Céline C Mooser Catherine C Nancey Stéphane S McCoy Kathy D KD Velin Dominique D Maillard Michel H MH

iScience 20200208 3

Expression of Toll-interacting protein (Tollip), a potent TLR modulator, decreases in patients with inflammatory bowel diseases (IBD), whereas Tollip<sup>-/-</sup> mice are susceptible to colitis. Tollip expression was shown to be reduced in sporadic adenoma. In contrast, we found variable Tollip expression in patients with colitis-associated adenomas. In Tollip<sup>-/-</sup> mice challenged to develop colitis-associated cancer (CAC), tumor formation was significantly reduced owing to decreased ...[more]

PMID: 32114379

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Project description:RationaleThe molecular mechanisms that regulate tuberculosis susceptibility and bacillus Calmette-Guérin (BCG)-induced immunity are mostly unknown. However, induction of the adaptive immune response is a critical step in host control of Mycobacterium tuberculosis. Toll-interacting protein (TOLLIP) is a ubiquitin-binding protein that regulates innate immune responses, including Toll-like receptor signaling, which initiate adaptive immunity. TOLLIP variation is associated with susceptibility to tuberculosis, but the mechanism by which it regulates tuberculosis immunity is poorly understood.ObjectivesTo identify functional TOLLIP variants and evaluate the role of TOLLIP variation on innate and adaptive immune responses to mycobacteria and susceptibility to tuberculosis.MethodsWe used human cellular immunology approaches to characterize the role of a functional TOLLIP variant on monocyte mRNA expression and M. tuberculosis-induced monocyte immune functions. We also examined the association of TOLLIP variation with BCG-induced T-cell responses and susceptibility to latent tuberculosis infection.Measurements and main resultsWe identified a functional TOLLIP promoter region single-nucleotide polymorphism, rs5743854, which was associated with decreased TOLLIP mRNA expression in infant monocytes. After M. tuberculosis infection, TOLLIP-deficient monocytes demonstrated increased IL-6, increased nitrite, and decreased bacterial replication. The TOLLIP-deficiency G/G genotype was associated with decreased BCG-specific IL-2+ CD4+ T-cell frequency and proliferation. This genotype was also associated with increased susceptibility to latent tuberculosis infection.ConclusionsTOLLIP deficiency is associated with decreased BCG-specific T-cell responses and increased susceptibility to tuberculosis. We hypothesize that the heightened antibacterial monocyte responses after vaccination of TOLLIP-deficient infants are responsible for decreased BCG-specific T-cell responses. Activating TOLLIP may provide a novel adjuvant strategy for BCG vaccination.

Project description:BackgroundColorectal cancer (CRC) is one of the three deadliest malignant tumors in the world, posing a severe hazard to human health. Nonetheless, the 5-year survival rate for advanced CRC remains unsatisfactory. Grid2 interacting protein (GRID2IP) is a Purkinje fiber postsynaptic scaffold protein implicated in a number of signal transduction pathways in the nervous system. Previous studies have shown that Grid2 is closely related to the occurrence and prognosis of gastric cancer and many other diseases. Therefore, we aim to identify the relationship between GRID2IP and the occurrence and prognosis of CRC.MethodsTranscriptome data were retrieved from The Cancer Genome Atlas (TCGA) database to analyze the differential expression of GRID2IP in a variety of malignant tumors and then validate it by quantitative real time polymerase chain reaction(Q-PCR) and Western Blot in HT29 and SW480 cells. "DESeq2" package was used to analyze the differentially expressed genes (DEGs) between the high- and low-GRID2IP subgroups. In relation to DEGs, Gene Ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis were performed. In addition, gene set enrichment analysis (GSEA) and single-sample gene set enrichment analysis (ssGSEA) were employed to examine DEGs-associated signaling pathways and GRID2IP-associated immune cell infiltration levels. Besides, overall survival (OS), disease-specific survival (DSS), and progression-free interval (PFI) were compared between the two subgroups using a Kaplan-Meier analysis. In addition, a prognostic model for GRID2IP and clinical characteristics was developed using the univariate Cox regression method. The "pRRophetic" package was applied to predict the drug sensitivity of different subgroups. Moreover, we also performed single-cell analysis of GRID2IP using the TISCH database.ResultsGRID2IP is upregulated in CRC patients. The rise of GRID2IP inhibits the invasion of tumor-associated immune cells resulting in a lower immune score. In addition, high GRID2IP expression was associated with poor prognosis in different clinical subgroups. Analysis of single cells revealed that GRID2IP was predominantly expressed in immune cells, myofibroblasts, and cancerous cells. In terms of chemotherapy drug sensitivity, the subgroup with high GRID2IP expression was less sensitive to gemcitabine.ConclusionsOur results suggest that rising GRID2IP promotes tumor-associated immune cell infiltration and suggests adverse outcomes in CRC patients, which may be a useful biomarker for determining the prognosis of CRC and a potential target molecule for CRC therapy.

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Toll-Interacting Protein Regulates Immune Cell Infiltration and Promotes Colitis-Associated Cancer.

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Toll-Interacting Protein Regulates Immune Cell Infiltration and Promotes Colitis-Associated Cancer.

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