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Identification of a genetic locus controlling bacteria-driven colitis and associated cancer through effects on innate inflammation.

Boulard O, Kirchberger S, Royston DJ, Maloy KJ, Powrie FM - J. Exp. Med. (2012)

Bottom Line: Chronic inflammation of the intestine has been associated with an elevated risk of developing colorectal cancer.Using a tumor-promoting model combining chronic Helicobacter hepaticus infection and the carcinogen azoxymethane, we found that Hiccs also regulates the frequency of colitis-associated neoplasia.Our study highlights the importance of innate immune cells and their genetic configuration in driving progression from inflammation toward cancer and opens the door for analysis of these pathways in human inflammatory disorders and associated cancers.

View Article: PubMed Central - HTML - PubMed

Affiliation: Translational Gastroenterology Unit, Nuffield Department of Clinical Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DU, England, UK.

ABSTRACT
Chronic inflammation of the intestine has been associated with an elevated risk of developing colorectal cancer. Recent association studies have highlighted the role of genetic predisposition in the etiology of colitis and started to unravel its complexity. However, the genetic factors influencing the progression from colon inflammation to tumorigenesis are not known. We report the identification of a genetic interval Hiccs that regulates Helicobacter hepaticus-induced colitis and associated cancer susceptibility in a 129.RAG(-/-) mouse model. The 1.7-Mb congenic interval on chromosome 3, containing eight genes and five microRNAs, renders susceptible mice resistant to colitis and reduces tumor incidence and multiplicity. Bone marrow chimera experiments showed that resistance is conferred by the hematopoietic compartment. Moreover, the Hiccs locus controls the induction of the innate inflammatory response by regulating cytokine expression and granulocyte recruitment by Thy1(+) innate lymphoid cells. Using a tumor-promoting model combining chronic Helicobacter hepaticus infection and the carcinogen azoxymethane, we found that Hiccs also regulates the frequency of colitis-associated neoplasia. Our study highlights the importance of innate immune cells and their genetic configuration in driving progression from inflammation toward cancer and opens the door for analysis of these pathways in human inflammatory disorders and associated cancers.

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Differential colitis susceptibility between C57BL/6.IL-10−/− and 129S6.IL-10−/− mice. Evaluation of colon inflammation after H. hepaticus infection for 2 mo. Data represent two pooled independent experiments. Three mice of each strain were also analyzed without H. hepaticus infection. Horizontal lines represent medians. **, P < 0.01, Mann-Whitney nonparametric test between B6 and 129 mice.
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fig2: Differential colitis susceptibility between C57BL/6.IL-10−/− and 129S6.IL-10−/− mice. Evaluation of colon inflammation after H. hepaticus infection for 2 mo. Data represent two pooled independent experiments. Three mice of each strain were also analyzed without H. hepaticus infection. Horizontal lines represent medians. **, P < 0.01, Mann-Whitney nonparametric test between B6 and 129 mice.

Mentions: As previously described (Erdman et al., 2003a,b), we found C57BL/6.RAG−/− (B6.RAG) mice to be strongly resistant to H. hepaticus–induced typhlocolitis, showing only limited inflammation of the cecum, reduced splenomegaly, and no colitis compared with the severe inflammation observed in H. hepaticus–infected 129S6.RAG−/− (129.RAG) mice (Fig. 1). The telomeric part of chromosome 3 has been identified in other models of colitis (using IL-10−/− and Gnai2−/− mice) as a major susceptibility locus (Beckwith et al., 2005; Borm et al., 2005). Consequently, we generated a novel congenic line on the 129.RAG background harboring a large interval of B6 origin on chromosome 3 (>40 Mb) delimited by the microsatellite markers D3Mit103 and D3Mit45 (Fig. 1 A). Upon H. hepaticus infection, phenotypic analysis of intercrossed mice from this 129S6.B6-(D3Mit103-D3Mit45).Rag2−/− congenic line (abbreviated 129.C3B.RAG or C3B) revealed that the B6 chromosome 3 interval conferred significant protection from colonic inflammation and splenomegaly but not from cecal inflammation (Fig. 1, B–D). Moreover, the similar protection between heterozygote 129/B6 and homozygote B6/B6 congenic mice indicated a clear dominant effect of the B6 chromosome 3 locus (Fig. 1, B–D). In these mice, intestinal inflammation was strongly reduced in the proximal and distal parts of the colon compared with littermate or 129.RAG controls. Some degree of inflammation could still be found in the mid colon (unpublished data). The differential phenotype in response to chronic H. hepaticus infection was not linked to a change in bacterial burden, as cecal colonization by H. hepaticus was found to be equivalent in infected B6.RAG, 129.RAG, and intercrossed 129.C3B.RAG mice (unpublished data). Using a lymphocyte-replete model of H. hepaticus infection in IL-10−/− mice, we found a marked reduction in colitis in B6.IL10−/− compared with 129.IL10−/− mice as described for the Cdcs 1 locus (Beckwith et al., 2005; Fig. 2). These results indicate that resistance to bacteria-induced colitis in the B6 compared with 129 strain extends to innate and lymphocyte replete models.


Identification of a genetic locus controlling bacteria-driven colitis and associated cancer through effects on innate inflammation.

Boulard O, Kirchberger S, Royston DJ, Maloy KJ, Powrie FM - J. Exp. Med. (2012)

Differential colitis susceptibility between C57BL/6.IL-10−/− and 129S6.IL-10−/− mice. Evaluation of colon inflammation after H. hepaticus infection for 2 mo. Data represent two pooled independent experiments. Three mice of each strain were also analyzed without H. hepaticus infection. Horizontal lines represent medians. **, P < 0.01, Mann-Whitney nonparametric test between B6 and 129 mice.
© Copyright Policy - openaccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC3405508&req=5

fig2: Differential colitis susceptibility between C57BL/6.IL-10−/− and 129S6.IL-10−/− mice. Evaluation of colon inflammation after H. hepaticus infection for 2 mo. Data represent two pooled independent experiments. Three mice of each strain were also analyzed without H. hepaticus infection. Horizontal lines represent medians. **, P < 0.01, Mann-Whitney nonparametric test between B6 and 129 mice.
Mentions: As previously described (Erdman et al., 2003a,b), we found C57BL/6.RAG−/− (B6.RAG) mice to be strongly resistant to H. hepaticus–induced typhlocolitis, showing only limited inflammation of the cecum, reduced splenomegaly, and no colitis compared with the severe inflammation observed in H. hepaticus–infected 129S6.RAG−/− (129.RAG) mice (Fig. 1). The telomeric part of chromosome 3 has been identified in other models of colitis (using IL-10−/− and Gnai2−/− mice) as a major susceptibility locus (Beckwith et al., 2005; Borm et al., 2005). Consequently, we generated a novel congenic line on the 129.RAG background harboring a large interval of B6 origin on chromosome 3 (>40 Mb) delimited by the microsatellite markers D3Mit103 and D3Mit45 (Fig. 1 A). Upon H. hepaticus infection, phenotypic analysis of intercrossed mice from this 129S6.B6-(D3Mit103-D3Mit45).Rag2−/− congenic line (abbreviated 129.C3B.RAG or C3B) revealed that the B6 chromosome 3 interval conferred significant protection from colonic inflammation and splenomegaly but not from cecal inflammation (Fig. 1, B–D). Moreover, the similar protection between heterozygote 129/B6 and homozygote B6/B6 congenic mice indicated a clear dominant effect of the B6 chromosome 3 locus (Fig. 1, B–D). In these mice, intestinal inflammation was strongly reduced in the proximal and distal parts of the colon compared with littermate or 129.RAG controls. Some degree of inflammation could still be found in the mid colon (unpublished data). The differential phenotype in response to chronic H. hepaticus infection was not linked to a change in bacterial burden, as cecal colonization by H. hepaticus was found to be equivalent in infected B6.RAG, 129.RAG, and intercrossed 129.C3B.RAG mice (unpublished data). Using a lymphocyte-replete model of H. hepaticus infection in IL-10−/− mice, we found a marked reduction in colitis in B6.IL10−/− compared with 129.IL10−/− mice as described for the Cdcs 1 locus (Beckwith et al., 2005; Fig. 2). These results indicate that resistance to bacteria-induced colitis in the B6 compared with 129 strain extends to innate and lymphocyte replete models.

Bottom Line: Chronic inflammation of the intestine has been associated with an elevated risk of developing colorectal cancer.Using a tumor-promoting model combining chronic Helicobacter hepaticus infection and the carcinogen azoxymethane, we found that Hiccs also regulates the frequency of colitis-associated neoplasia.Our study highlights the importance of innate immune cells and their genetic configuration in driving progression from inflammation toward cancer and opens the door for analysis of these pathways in human inflammatory disorders and associated cancers.

View Article: PubMed Central - HTML - PubMed

Affiliation: Translational Gastroenterology Unit, Nuffield Department of Clinical Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DU, England, UK.

ABSTRACT
Chronic inflammation of the intestine has been associated with an elevated risk of developing colorectal cancer. Recent association studies have highlighted the role of genetic predisposition in the etiology of colitis and started to unravel its complexity. However, the genetic factors influencing the progression from colon inflammation to tumorigenesis are not known. We report the identification of a genetic interval Hiccs that regulates Helicobacter hepaticus-induced colitis and associated cancer susceptibility in a 129.RAG(-/-) mouse model. The 1.7-Mb congenic interval on chromosome 3, containing eight genes and five microRNAs, renders susceptible mice resistant to colitis and reduces tumor incidence and multiplicity. Bone marrow chimera experiments showed that resistance is conferred by the hematopoietic compartment. Moreover, the Hiccs locus controls the induction of the innate inflammatory response by regulating cytokine expression and granulocyte recruitment by Thy1(+) innate lymphoid cells. Using a tumor-promoting model combining chronic Helicobacter hepaticus infection and the carcinogen azoxymethane, we found that Hiccs also regulates the frequency of colitis-associated neoplasia. Our study highlights the importance of innate immune cells and their genetic configuration in driving progression from inflammation toward cancer and opens the door for analysis of these pathways in human inflammatory disorders and associated cancers.

Show MeSH
Related in: MedlinePlus