Summary Colitis associated cancer (CAC) is the most serious complication of inflammatory bowel disease. Pro-inflammatory cytokines were suggested to regulate pre-neoplastic growth during CAC tumorigenesis. Interleukin 6 (IL-6) is a multifunctional NF-κB–regulated cytokine which acts on epithelial and immune cells. Using genetic tools we now demonstrate that IL-6 is a critical tumor promoter during early CAC tumorigenesis. In addition to enhancing proliferation of tumor initiating cells, IL-6 produced by lamina propria myeloid cells protects normal and pre-malignant intestinal epithelial cells (IEC) from apoptosis. The proliferative and survival effects of IL-6 are largely mediated by transcription factor STAT3, whose IEC-specific ablation has profound impact on CAC tumorigenesis. Thus, the NF-κB-IL-6-STAT3 cascade is an important regulator of the proliferation and survival of tumor initiating IEC.

The cytokine transforming growth factor-beta (TGF-beta) converts naïve T cells into regulatory T (Treg) cells that prevent autoimmunity. However, in the presence of interleukin-6 (IL-6), TGF-beta has also been found to promote the differentiation of naïve T lymphocytes into proinflammatory IL-17 cytokine-producing T helper 17 (T(H)17) cells, which promote autoimmunity and inflammation. This raises the question of how TGF-beta can generate such distinct outcomes. We identified the vitamin A metabolite retinoic acid as a key regulator of TGF-beta-dependent immune responses, capable of inhibiting the IL-6-driven induction of proinflammatory T(H)17 cells and promoting anti-inflammatory Treg cell differentiation. These findings indicate that a common metabolite can regulate the balance between pro- and anti-inflammatory immunity.

Approximately 2% of colorectal cancer is linked to pre-existing inflammation known as colitis-associated cancer, but most develops in patients without underlying inflammatory bowel disease. Colorectal cancer often follows a genetic pathway whereby loss of the adenomatous polyposis coli (APC) tumour suppressor and activation of β-catenin are followed by mutations in K-Ras, PIK3CA and TP53, as the tumour emerges and progresses1,2. Curiously, however, ‘inflammatory signature’ genes characteristic of colitis-associated cancer are also upregulated in colorectal cancer3,4. Further, like most solid tumours, colorectal cancer exhibits immune/inflammatory infiltrates5, referred to as ‘tumour elicited inflammation’6. Although infiltrating CD4+ TH1 cells and CD8+ cytotoxic T cells constitute a positive prognostic sign in colorectal cancer7,8, myeloid cells and T-helper interleukin (IL)-17-producing (TH17) cells promote tumorigenesis5,6, and a ‘TH17 expression signature’ in stage I/II colorectal cancer is associated with a drastic decrease in disease-free survival9. Despite its pathogenic importance, the mechanisms responsible for the appearance of tumour-elicited inflammation are poorly understood. Many epithelial cancers develop proximally to microbial communities, which are physically separated from immune cells by an epithelial barrier10. We investigated mechanisms responsible for tumour-elicited inflammation in a mouse model of colorectal tumorigenesis, which, like human colorectal cancer, exhibits upregulation of IL-23 and IL-17. Here we show that IL-23 signalling promotes tumour growth and progression, and development of a tumoural IL-17 response. IL-23 is mainly produced by tumour-associated myeloid cells that are likely to be activated by microbial products, which penetrate the tumours but not adjacent tissue. Both early and late colorectal neoplasms exhibit defective expression of several barrier proteins. We propose that barrier deterioration induced by colorectal-cancer-initiating genetic lesions results in adenoma invasion by microbial products that trigger tumour-elicited inflammation, which in turn drives tumour growth.

The intraepithelial lymphocytes (IELs) that reside within the epithelium of the intestine form one of the main branches of the immune system. As IELs are located at this critical interface between the core of the body and the outside environment, they must balance protective immunity with an ability to safeguard the integrity of the epithelial barrier: failure to do so would compromise homeostasis of the organism. In this Review, we address how the unique development and functions of intestinal IELs allow them to achieve this balance.

Regulatory T cells (T reg cells) that express the transcription factor Foxp3 suppress the activity of other cells. Here we show that interleukin 10 (IL-10) produced by CD11b + myeloid cells in recombination-activating gene 1-deficient (Rag1 −/− ) recipient mice was needed to prevent the colitis induced by transferred CD4 + CD45RB hi T cells. In Il10 −/− Rag1 −/− mice, T reg cells failed to maintain Foxp3 expression and regulatory activity. The loss of Foxp3 expression occurred only in recipients with colitis, which indicates that the requirement for IL-10 is manifested in the presence of inflammation. IL-10 receptor-deficient (Il10rb −/− ) T reg cells also failed to maintain Foxp3 expression, which suggested that host IL-10 acted directly on the T reg cells. Our data indicate that IL-10 released from myeloid cells acts in a paracrine manner on T reg cells to maintain Foxp3 expression. CD4 + regulatory T cells (T reg cells) express the transcription factor Foxp3 (A002750), which is required for their suppressive function. A T cell-transfer model of colitis has been widely used to study the function of T reg cells in vivo. When CD4 + CD45RB hi T cells are transferred into immunodeficient mice, some of the transferred T cells secrete proinflammatory cytokines and induce an inflammatory bowel disease-like syndrome 1,2 . Cotransfer of sufficient numbers of T reg cells can prevent or even cure this disease 3,4 . The transferred T reg cell populations expand considerably in vivo, and most maintain Foxp3 expression 5,6 .Mice deficient in interleukin 10 (IL-10 (A001243); Il10 −/− mice) or the IL-10 receptor β-chain (IL-10Rβ (A001245); Il10rb −/− mice) develop spontaneous inflammation of the large intestine, a process dominated by a T helper type 1 immune response7 ,8 . Many cell types can produce IL-10, however, and therefore the IL-10 source(s) needed to prevent inflammation must be identified. Much emphasis has been placed on the role of IL-10 released by CD4 + T cells, and in fact mice with conditional deletion of IL-10 in the CD4 + subset develop spontaneous inflammation of the intestine 9 . Mice with deletion of IL-10 solely in Foxp3 + cells also develop inflammation in the intestine and elsewhere, although the pathogenesis is less intense than that in mice completely lacking . Transgenic mice that overexpress IL-10 in intestinal epithelial cells are protected from colitis11, which suggests that IL-10 from nonlymphoid sources can be beneficial, although altered expression in the transgenic mice may not be physiologically relevant. NIH Public AccessTo further elucidate the cellular and molecular basis of the function of IL-10 in regulating colitis, we used the T cell-transfer model described above. We found that IL-10 from nonlymphoid cells, particularly CD11b + CD11c + cells, had an unexpectedly important influence on the development of colitis. Furthermore, we provide evidence that this IL-10 acted in part on T reg cells to maintain their expression of Foxp3, which was otherwise lost in inflammatory condit...