0000000000319655
AUTHOR
Maximilian J. Waldner
Assessment of Tumor Development and Wound Healing Using Endoscopic Techniques in Mice
Mouse models of intestinal inflammation and colon cancer are valuable tools to gain insights into the pathogenesis of the corresponding human diseases. Recently, in vivo mouse endoscopy has been developed, allowing not only the high-resolution monitoring and scoring of experimental disease development, but also enables the investigator to perform manipulations, including local injection of reagents or the taking of biopsies for molecular and histopathologic analyses. Chromoendoscopic staining with methylene blue enables visualization of the crypt structure and allows discrimination between inflammatory and neoplastic changes. The development of endoscopic techniques in live mice opened new …
Novel cytokine-targeted therapies and intestinal inflammation
Several cytokines have been identified as critical mediators of chronic inflammation in inflammatory bowel disease (IBD) and biological therapies that target these molecules have been developed during recent years. Thereby, anti-TNF agents have noticeably improved the treatment of patients with IBD in comparison to conventional therapy. Furthermore, initial clinical trials showed promising results with anti-IL-6 and anti-IL-12/IL-23 agents. In addition to these well-known mediators of IBD, various novel cytokines have been described as critical during the pathogenesis of IBD in recent experimental studies and therapeutic targeting of these cytokines could provide new strategies for human di…
Chemically induced mouse models of colitis.
Crohn's disease (CD) and ulcerative colitis (UC), both of which are referred to as inflammatory bowel disease (IBD), are chronic inflammatory disorders of the gastrointestinal tract that have characteristic clinical, pathological, endoscopic, and radiologic features. Knowledge about the pathogenesis of IBD has dramatically increased in recent years based in part on the use of experimental models of IBD. Although none of these models exactly mimics the human disorder, they have proven to be useful for studying many important aspects of these conditions. Detailed in this unit is a description of the most commonly used chemically induced mouse models of IBD. These include trinitrobenzene sulfo…
Interleukin-33-Dependent Innate Lymphoid Cells Mediate Hepatic Fibrosis
SummaryLiver fibrosis is a consequence of chronic liver diseases and thus a major cause of mortality and morbidity. Clinical evidence and animal studies suggest that local tissue homeostasis is disturbed due to immunological responses to chronic hepatocellular stress. Poorly defined stress-associated inflammatory networks are thought to mediate gradual accumulation of extracellular-matrix components, ultimately leading to fibrosis and liver failure. Here we have reported that hepatic expression of interleukin-33 (IL-33) was both required and sufficient for severe hepatic fibrosis in vivo. We have demonstrated that IL-33’s profibrotic effects related to activation and expansion of liver resi…
Antibodies against tumor necrosis factor (TNF) induce T-cell apoptosis in patients with inflammatory bowel diseases via TNF receptor 2 and intestinal CD14⁺ macrophages.
Background & Aims The anti–tumor necrosis factor (TNF) antibodies infliximab, adalimumab, and certolizumab pegol have proven clinical efficacy in Crohn's disease. Here, we assessed the effects of anti-TNF antibodies on apoptosis in inflammatory bowel disease (IBD). Methods CD14 + macrophages and CD4 + T cells were isolated from peripheral blood and lamina propria mononuclear cells from patients with IBD and control patients. Cell surface markers and apoptosis were assessed by immunohistology and fluorescence-activated cell sorting techniques. Results Lamina propria CD14 + macrophages showed significantly more frequent and higher membrane-bound TNF (mTNF) expression than CD4 + T cells in IBD…
Perforin deficiency attenuates inflammation and tumor growth in colitis-associated cancer
Background: Patients with inflammatory bowel disease (IBD) have a markedly increased risk to develop colon cancer, but there are only limited data about the host antitumor response in such colitis-associated cancer. In the present study we aimed at assessing the role of perforin-dependent effector mechanisms in the immune response in a murine model of colitis-associated colon cancer. Methods: Wildtype and perforin-deficient mice were analyzed in a mouse model of colitis-associated colon cancer using azoxymethane (AOM) and dextran sodium sulfate (DSS). Results: Tumors of wildtype mice showed infiltration of CD4+, CD8+ T cells, natural killer (NK) cells, high numbers of apoptotic cells, and e…
VEGF receptor signaling links inflammation and tumorigenesis in colitis-associated cancer.
Inflammation drives expression of VEGFR2, which is expressed on and drives growth of tumor cells in colitis-associated cancer.
Caspase-8 regulates TNF-alpha induced epithelial necroptosis and terminal ileitis
Two groups identify the regulation of death-receptor-induced necroptosis as an epithelial intrinsic mechanism that is important for the maintenance of immune homeostasis and the prevention of intestinal inflammation in mice. Welz et al. describe an unexpected physiological function for FADD (Fas-associated protein with death domain), an adaptor protein required for death-receptor-induced apoptosis. Mice with intestinal epithelial specific knockout of FADD develop severe colon inflammation due to increased death of FADD-deficient colonic epithelial cells. Gunther et al. report a novel and unexpected function of caspase-8 in maintaining immune homeostasis in the gut. Caspase-8 expression by g…