CD4+ CD25+ Regulatory T Lymphocytes Inhibit Microbially Induced Colon Cancer in Rag2-Deficient Mice

Erdman, Susan E.; Poutahidis, Theofilos; Tomczak, Michal; Rogers, Arlin B.; Cormier, Kathleen S.; Plank, Benjamin; Horwitz, Bruce H.; Fox, James G.

doi:10.1016/s0002-9440(10)63863-1

Cited by 280 publications

(320 citation statements)

References 57 publications

(74 reference statements)

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“…This suggestion is supported by recent observations that purified populations of CD4 ϩ CD25 ϩ regulatory T cells are able to inhibit the ability of H. hepaticus to induce colitis in Rag-deficient mice (12,13). However, little is known regarding the factors that regulate the inflammatory response to H. hepaticus infection.…”

Section: Nf-b Is Required Within the Innate Immune System To Inhibit mentioning

confidence: 81%

NF-κB Is Required Within the Innate Immune System to Inhibit Microflora-Induced Colitis and Expression of IL-12 p40

Tomczak

Erdman

Poutahidis

et al. 2003

The Journal of Immunology

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We have previously presented evidence demonstrating that mice deficient in NF-κB subunits are susceptible to colitis induced by the pathogenic enterohepatic Helicobacter species, H. hepaticus. However, it has not been determined whether NF-κB is required within inhibitory lymphocyte populations, within cells of the innate immune system, or both, to suppress inflammation. To examine these issues, we have performed a series of adoptive transfer experiments using recombination-activating gene (Rag)-2−/− or p50−/−p65+/−Rag-2−/− mice as hosts for wild-type (WT) and p50−/−p65+/− lymphocyte populations. We have shown that although the ability of H. hepaticus to induce colitis in Rag-2−/− mice is inhibited by the presence of either WT or p50−/−p65+/− splenocytes, these splenocyte populations are unable to suppress H. hepaticus-induced colitis in p50−/−p65+/−Rag-2−/− mice. Colitis in these animals is characterized by increased expression of inflammatory cytokines including IL-12 p40, and depletion of IL-12 p40 from p50−/−p65+/− mice ameliorates H. hepaticus-induced disease. Consistent with a primary defect in the regulation of IL-12 expression, H. hepaticus induced markedly higher levels of IL-12 p40 in p50−/−p65+/− macrophages than in WT macrophages. These results suggest that inhibition of H. hepaticus-induced IL-12 p40 expression by NF-κB subunits is critical to preventing colonic inflammation in response to inflammatory microflora.

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Section: Nf-b Is Required Within the Innate Immune System To Inhibit mentioning

confidence: 81%

NF-κB Is Required Within the Innate Immune System to Inhibit Microflora-Induced Colitis and Expression of IL-12 p40

Tomczak

Erdman

Poutahidis

et al. 2003

The Journal of Immunology

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“…Taken together, these histopathological and gene expression data indicate that pharmacological inhibition of SMO by MDL 72527 reduces ETBFassociated intestinal chronic inflammation and proliferation. of the immune response to bacteria that may be involved in either promoting or protecting against intestinal inflammation and carcinogenesis (31)(32)(33)(34)(35)(36). The importance of bacterially-induced ROS in inflammation-associated carcinogenesis was demonstrated in mice lacking the H 2 O 2 detoxification enzymes gpx-1 and gpx-2.…”

Section: Resultsmentioning

confidence: 99%

Polyamine catabolism contributes to enterotoxigenic Bacteroides fragilis -induced colon tumorigenesis

Goodwin¹,

Shields²,

Wu³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

453

325

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It is estimated that the etiology of 20-30% of epithelial cancers is directly associated with inflammation, although the direct molecular events linking inflammation and carcinogenesis are poorly defined. In the context of gastrointestinal disease, the bacterium enterotoxigenic Bacteroides fragilis (ETBF) is a significant source of chronic inflammation and has been implicated as a risk factor for colorectal cancer. Spermine oxidase (SMO) is a polyamine catabolic enzyme that is highly inducible by inflammatory stimuli resulting in increased reactive oxygen species (ROS) and DNA damage. We now demonstrate that purified B. fragilis toxin (BFT) upregulates SMO in HT29/c1 and T84 colonic epithelial cells, resulting in SMO-dependent generation of ROS and induction of γ-H2A.x, a marker of DNA damage. Further, ETBF-induced colitis in C57BL/6 mice is associated with increased SMO expression and treatment of mice with an inhibitor of polyamine catabolism, N 1 ,N 4 -bis(2,3-butandienyl)-1,4-butanediamine (MDL 72527), significantly reduces ETBF-induced chronic inflammation and proliferation. Most importantly, in the multiple intestinal neoplasia (Min) mouse model, treatment with MDL 72527 reduces ETBF-induced colon tumorigenesis by 69% (P < 0.001). The results of these studies indicate that SMO is a source of bacteria-induced ROS directly associated with tumorigenesis and could serve as a unique target for chemoprevention.inflammatory bowel diseases | adenomatous polyposis coli I t is estimated that chronic inflammation associated with microbial infection directly contributes to the etiology of about 20% of epithelial cancers. The chronic inflammatory microenvironment is characterized by immune dysregulation and elevated levels of reactive oxygen species [ROS; including superoxide, hydrogen peroxide (H 2 O 2 ), and singlet oxygen]. These features result in activation of stress response pathways and oncogenes, down-regulation of tumor suppressor genes, cell and tissue damage, and contribute to tumor initiation, promotion, and progression. However, the precise molecular links between inflammation and carcinogenesis remain to be clarified (1, 2).In the colon, alterations in the physiological balance between the diverse and abundant microbiota (w10 12 organisms per gram feces) and the host are a common source of inflammation. Bacteroides spp comprise a significant proportion of colonic commensal bacteria and members of this group include symbionts and the leading human anaerobic pathogen, Bacteroides fragilis. Enterotoxigenic B. fragilis (ETBF) represent a molecular subtype characterized by a single unique virulence determinant, the production and secretion of a 20-kDa metalloprotease enterotoxin (B. fragilis toxin; BFT). ETBF have been epidemiologically associated with acute diarrheal diseases in humans and livestock, inflammatory bowel diseases (IBD), and colorectal cancer (reviewed in ref.3). Exposure of intestinal epithelial cell lines to BFT results in cleavage of the cell adhesion and tumor suppressor protein E-cadherin, ...

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“…To assess the contribution of NO production to colon cancer development, Rag2 Ϫ/Ϫ and wt mice were infected with H. hepaticus (16,18). Total NO production was measured by urinary nitrate (NO 3 Ϫ ) excretion (11).…”

Section: Resultsmentioning

confidence: 99%

“…Roles for chronic bacterial infection in IBD and colon cancer have been identified recently in recombinase-activating gene-2-deficient mice (Rag2 Ϫ/Ϫ ), which completely lack functional lymphocytes (16-18). We have exploited this mouse model of chronic IBDassociated cancer for studies of the role of NO and its products because it emulates naturally occurring inflammatory events in humans (16,19,20).Rag2 Ϫ/Ϫ mice have been used to assess functions of lymphocytes by adoptive transfer. Populations of CD4 ϩ T cells with low or high expression of CD45RB (17,21, 22) or CD25 (16,18,23,24) prevent or accelerate colitis in these animals.…”

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confidence: 99%

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confidence: 99%

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Nitric oxide and TNF-α trigger colonic inflammation and carcinogenesis in Helicobacter hepaticus -infected, Rag2 -deficient mice

Erdman¹,

Rao²,

Poutahidis

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

168

217

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Recombinase-activating gene-2-deficient (Rag2 ؊/؊ ) mice lacking functional lymphocytes provide a useful model of chronic inflammatory bowel disease-emulating events in human colon cancer. Infection of Rag2 ؊/؊ mice with Helicobacter hepaticus led to accumulation of macrophages and neutrophils in the colon, a process temporally related to up-regulation of tissue inducible nitric oxide synthase (iNOS) expression at the site of infection and increased nitric oxide (NO) production, as evidenced by urinary excretion of nitrate. Progressive development of increasingly severe inflammation, hyperplasia, dysplasia, and cancer accompanied these changes. Concurrent administration of an iNOS inhibitor prevented NO production and abrogated epithelial pathology and inhibited the onset of cancer. The presence of Gr-1 ؉ neutrophils and elevated tumor necrosis factor-␣ (TNF-␣) expression in colon were required for increased iNOS expression and cancer, whereas interleukin-10 (IL-10) down-regulated TNF-␣ and iNOS expression and suppressed cancer. Anti-inflammatory CD4 ؉ regulatory lymphocytes also down-regulated iNOS and reduced cancer formation. Collectively, these results confirm essential roles for inflammation, increased TNF-␣ expression, and elevated NO production in colon carcinogenesis.colorectal cancer ͉ IBD ͉ innate immunity C hronic Helicobacter pylori infection in humans leads to gastritis and has been established as a causative agent for human gastric cancer (1). Inflammatory bowel diseases (IBDs), such as Crohn's disease and ulcerative colitis, also increase risk for colon cancer (2, 3). Generation of nitric oxide (NO) by inducible NO synthase (iNOS) is a central feature of chronic inflammatory diseases in the gastrointestinal tract (4-9), but precise mechanistic roles for NO in colon cancer development remain undefined.Colon cancer patients exhibit evidence of nitrosative and oxidative stresses that increase cancer risk (10), resulting from mutagenic reactive oxygen and nitrogen species derived from NO generated by immune cells (6,(11)(12)(13)(14)(15). Roles for chronic bacterial infection in IBD and colon cancer have been identified recently in recombinase-activating gene-2-deficient mice (Rag2 Ϫ/Ϫ ), which completely lack functional lymphocytes (16-18). We have exploited this mouse model of chronic IBDassociated cancer for studies of the role of NO and its products because it emulates naturally occurring inflammatory events in humans (16,19,20).Rag2 Ϫ/Ϫ mice have been used to assess functions of lymphocytes by adoptive transfer. Populations of CD4 ϩ T cells with low or high expression of CD45RB (17,21, 22) or CD25 (16,18,23,24) prevent or accelerate colitis in these animals. In wild-type (wt) mice, protection against inflammatory pathology induced by bacterial infection has been attributed to interleukin-10 (IL-10) and IL-10-dependent functions of CD4 ϩ cells (18,20,25,26). Collectively, this evidence forms the rationale for the hypothesis that NO overproduction comprises a linkage between Helicobacter hepaticus-i...

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CD4+ CD25+ Regulatory T Lymphocytes Inhibit Microbially Induced Colon Cancer in Rag2-Deficient Mice

Cited by 280 publications

References 57 publications

NF-κB Is Required Within the Innate Immune System to Inhibit Microflora-Induced Colitis and Expression of IL-12 p40

NF-κB Is Required Within the Innate Immune System to Inhibit Microflora-Induced Colitis and Expression of IL-12 p40

Polyamine catabolism contributes to enterotoxigenic Bacteroides fragilis -induced colon tumorigenesis

Nitric oxide and TNF-α trigger colonic inflammation and carcinogenesis in Helicobacter hepaticus -infected, Rag2 -deficient mice

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