A link between inflammation and cancer has long been suspected, but its molecular nature remained ill defined. A key player in inflammation is transcription factor NF-kappaB whose activity is triggered in response to infectious agents and proinflammatory cytokines via the IkappaB kinase (IKK) complex. Using a colitis-associated cancer model, we show that although deletion of IKKbeta in intestinal epithelial cells does not decrease inflammation, it leads to a dramatic decrease in tumor incidence without affecting tumor size. This is linked to increased epithelial apoptosis during tumor promotion. Deleting IKKbeta in myeloid cells, however, results in a significant decrease in tumor size. This deletion diminishes expression of proinflammatory cytokines that may serve as tumor growth factors, without affecting apoptosis. Thus, specific inactivation of the IKK/NF-kappaB pathway in two different cell types can attenuate formation of inflammation-associated tumors. In addition to suppressing apoptosis in advanced tumors, IKKbeta may link inflammation to cancer.

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.

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.

Ulcerative colitis is an idiopathic, chronic inflammatory disorder of the colonic mucosa, which starts in the rectum and generally extends proximally in a continuous manner through part of, or the entire, colon; however, some patients with proctitis or left-sided colitis might have a caecal patch of inflammation. Bloody diarrhoea is the characteristic symptom of the disease. The clinical course is unpredictable, marked by alternating periods of exacerbation and remission. In this Seminar we discuss the epidemiology, pathophysiology, diagnostic approach, natural history, medical and surgical management, and main disease-related complications of ulcerative colitis, and briefly outline novel treatment options. Enhanced understanding of how the interaction between environmental factors, genetics, and the immune system results in mucosal inflammation has increased knowledge of disease pathophysiology. We provide practical therapeutic algorithms that are easily applicable in daily clinical practice, emphasising present controversies in treatment management and novel therapies.

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The intestinal epithelium is in direct contact with a vast microbiota, yet little is known about how epithelial cells defend the host against the heavy bacterial load. To address this question we studied Paneth cells, a key small intestinal epithelial lineage. We found that Paneth cells directly sense enteric bacteria through cell-autonomous MyD88-dependent toll-like receptor (TLR) activation, triggering expression of multiple antimicrobial factors. Paneth cells were essential for controlling intestinal barrier penetration by commensal and pathogenic bacteria. Furthermore, Paneth cell-intrinsic MyD88 signaling limited bacterial penetration of host tissues, revealing a role for epithelial MyD88 in maintaining intestinal homeostasis. Our findings establish that gut epithelia actively sense enteric bacteria and play an essential role in maintaining host-microbial homeostasis at the mucosal interface.commensal bacteria ͉ epithelium ͉ innate immunity ͉ intestine ͉ toll-like receptors H umans harbor nearly 100 trillion intestinal bacteria that are essential for health. Millions of years of coevolution have molded this human-microbe interaction into a symbiotic relationship in which gut bacteria make essential contributions to human nutrient metabolism and in return occupy a nutrient-rich environment (1). However, bacterial invasion of tissue can result in breakdown of this symbiotic association and lead to pathologies such as inflammatory bowel disease (2). Intestinal epithelia constitute the major interface between the microbiota and internal host tissues. Despite the enormous numbers of commensal bacteria, microbial incursions across mucosal surfaces are relatively rare, suggesting that intestinal epithelia harbor highly effective mechanisms for controlling microbial interactions with the host mucosal interface. However, little is known about how intestinal epithelial cells maintain homeostasis with vast, complex populations of enteric bacteria.The Paneth cell is a specialized small intestinal epithelial lineage that resides at the base of crypts of Lieberkühn and contributes to intestinal innate immunity by secreting a diverse repertoire of antimicrobial proteins (3). Several antimicrobial factors in Paneth cells are expressed under the control of indigenous microorganisms (4, 5). In addition, ex vivo studies on isolated small intestinal crypts indicate that secretion of antimicrobial products is triggered by bacterial signals (3). However, itis not yet clear whether Paneth cells detect bacteria through cell-autonomous mechanisms. Furthermore, although Paneth cells are known to secrete abundant antimicrobial factors (3), the in vivo functional role of Paneth cells in maintaining homeostasis with commensal bacterial populations has not been established.In this report, we show that Paneth cells detect enteric bacteria through cell-autonomous MyD88 activation, triggering expression of multiple antimicrobial factors. We show that Paneth cell-intrinsic MyD88 signaling limits bacterial penetration of host tissues, disclo...

IKKbeta-dependent NF-kappaB activation plays a key role in innate immunity and inflammation, and inhibition of IKKbeta has been considered as a likely anti-inflammatory therapy. Surprisingly, however, mice with a targeted IKKbeta deletion in myeloid cells are more susceptible to endotoxin-induced shock than control mice. Increased endotoxin susceptibility is associated with elevated plasma IL-1beta as a result of increased pro-IL-1beta processing, which was also seen upon bacterial infection. In macrophages enhanced pro-IL-1beta processing depends on caspase-1, whose activation is inhibited by NF-kappaB-dependent gene products. In neutrophils, however, IL-1beta secretion is caspase-1 independent and depends on serine proteases, whose activity is also inhibited by NF-kappaB gene products. Prolonged pharmacologic inhibition of IKKbeta also augments IL-1beta secretion upon endotoxin challenge. These results unravel an unanticipated role for IKKbeta-dependent NF-kappaB signaling in the negative control of IL-1beta production and highlight potential complications of long-term IKKbeta inhibition.

Variants of NOD2, an intracellular sensor of bacteria-derived muramyl dipeptide (MDP), increase susceptibility to Crohn's disease (CD). These variants are thought to be defective in activation of nuclear factor kappaB (NF-kappaB) and antibacterial defenses, but CD clinical specimens display elevated NF-kappaB activity. To illuminate the pathophysiological function of NOD2, we introduced such a variant to the mouse Nod2 locus. Mutant mice exhibited elevated NF-kappaB activation in response to MDP and more efficient processing and secretion of the cytokine interleukin-1beta (IL-1beta). These effects are linked to increased susceptibility to bacterial-induced intestinal inflammation and identify NOD2 as a positive regulator of NF-kappaB activation and IL-1beta secretion.