Emergence of perianal fistulizing disease in the SAMP1/YitFc mouse, a spontaneous model of chronic ileitis

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223

Probiotic formulations are widely available and have a variety of proposed beneficial effects, including promotion of gut health. The mechanisms of action of probiotic bacteria in the intestine are still unclear but are generally attributed to an antiinflammatory effect. Here, we demonstrate that the multiple probiotic formulation VSL#3 prevents the onset of intestinal inflammation by local stimulation of epithelial innate immune responses (i.e., increased production of epithelial-derived TNF-α and restoration of epithelial barrier function in vivo). We also demonstrate that probiotic bacteria stimulate epithelial production of TNF-α and activate NF-κB in vitro. Our results support the hypothesis that probiotics promote gut health through stimulation, rather than suppression, of the innate immune system. Furthermore, our findings provide the perspective that defects in innate immunity may play a critical role in the pathogenesis and progression of intestinal disorders, such as inflammatory bowel disease.

mentioning

confidence: 56%

Probiotics promote gut health through stimulation of epithelial innate immunity

Pagnini

Saeed

Bamias

et al. 2009

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298

223

“…Our in vitro findings indicate that such an association would lead to proliferation of effector lymphocytes in the inflamed mucosa. Expansion of lamina propria T cells is a central characteristic of both experimental ileitis (including SAMP1͞YitFc and TNF ⌬ARE mice) and the human condition (16,17,21). Binding of TL1A to DR3 on mucosal lymphocytes would lead to increased secretion of IFN-␥ from the lymphocytes.…”

Section: Discussionmentioning

confidence: 99%

“…We tested our hypothesis in two immunogenetically diverse models of chronic ileitis, namely SAMP1͞YitFc and TNF ⌬ARE mice. Both models share clinical, pathological, and immunological characteristics with CD, and are considered to be representative of the human condition (16,17). We measured the relative expression of the mRNA for tmDR3 in the terminal ileum of inflamed SAMP1͞YitFc mice and compared it to the levels in both uninflamed control AKR and young SAMP1͞YitFc mice before the development of ileitis, with the latter serving as the internal, strain-specific control.…”

Section: Chronic Small Intestinal Inflammation Is Associated With Mucmentioning

confidence: 99%

“…In this study, we investigated the hypothesis that interaction(s) between TL1A and DR3 participate in the pathogenesis of murine chronic small intestinal inflammation. Using two mouse models of CD (16)(17)(18), we have demonstrated that expression of DR3 is significantly up-regulated during chronic ileitis in an inflammation-specific manner. This up-regulation involves alternative splicing of the mRNA that encodes DR3, which results in predominant expression of the transmembrane (tm) form of the receptor in preference to the soluble form.…”

mentioning

confidence: 97%

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Role of TL1A and its receptor DR3 in two models of chronic murine ileitis

Bamias

Mishina

Nyce

et al. 2006

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148

164

TL1A is a TNF-like cytokine that binds to the death-domain receptor (DR)3 and provides costimulatory signals to activated lymphocytes. Through this interaction, TL1A induces secretion of IFN-␥ and may, therefore, participate in the development of T helper-1-type effector responses. In this study, we investigated whether interactions between TL1A and DR3 are involved in the pathogenesis of chronic murine ileitis. We demonstrate that alternative splicing of DR3 mRNA takes place during the activation of lymphocytes, which results in up-regulation of the complete͞transmembrane (tm) form of DR3. Using two immunogenetically distinct animal models of Crohn's disease, we demonstrate that induction of intestinal inflammation is associated with significant up-regulation of TL1A and tm DR3 in the inflamed mucosa. In addition, within isolated lamina propria mononuclear cells from mice with inflammation, TL1A is primarily expressed on CD11c high dendritic cells. We also report that TL1A acts preferentially on memory CD4 ؉ ͞CD45RB lo murine lymphocytes by significantly inducing their proliferation, whereas it does not affect the proliferation of the naïve CD4 ؉ ͞ CD45RB hi T helper cell subpopulation. Finally, we demonstrate that TL1A synergizes with both the cytokine-dependent IL-12͞IL-18 pathway and with low-dose stimulation of the T cell receptor to significantly induce the secretion of IFN-␥ via an IL-18-independent pathway. Our results raise the possibility that interaction(s) between TL1A expressed on antigen-presenting cells and tm DR3 on lymphocytes may be of particular importance for the pathogenesis of chronic inflammatory conditions that depend on IFN-␥ secretion, including inflammatory bowel disease. Blockade of the TL1A͞DR3 pathway may, therefore, offer therapeutic opportunities in Crohn's disease.Crohn's disease ͉ cytokines ͉ mucosal inflammation T he differentiation of naïve CD4 ϩ lymphocytes into IFN-␥-secreting Th1 ''effector'' cells is a multistep process that involves several cell types, costimulatory molecules, transcription factors, and secreted cytokines (1). Antigen-presenting cell (APC)-derived IL-12 is essential for the induction of IFN-␥, an effect that is greatly enhanced by IL-18 (2). IL-12 up-regulates T-bet, a transcription factor that is critical for the stabilization of a T helper (Th)1-polarized phenotype (3). Recently, additional cytokines that play prominent roles during Th1 responses have been described, such as IL-27 and IL-23 (4). Engagement of the T cell receptor (TCR) provides further signals for the induction of IFN-␥, both in parallel to and independently of cytokinemediated pathways (1).Members of the TNF and TNF-receptor superfamilies of proteins (TNFSFPs and TNFRSFPs, respectively) are abundantly expressed in the immune system, and are critically involved in the differentiation, proliferation, and apoptosis of immune cells (5). Several members of these families induce secretion of IFN-␥ upon ligand͞receptor binding, thereby enhancing Th1-type responses (6-8). TL1A (TNFSPF15) is a r...

“…To determine whether IL-33 contributes to the development chronic intestinal inflammation, SAMP mice were studied at a preinflammatory state (4 wk), at the onset of inflammation (12 wk), and during established disease (>20 wk) (19). Increasing IL-33 mRNA and protein (both f-and c-IL-33) levels were detected in full-thickness ilea of SAMP mice vs. AKR (parental control strain) with age (20 wks, P < 0.01) (Fig.…”

Section: Il-33 Is Up-regulated and Correlates With Disease Severity Imentioning

confidence: 99%

Epithelial-derived IL-33 and its receptor ST2 are dysregulated in ulcerative colitis and in experimental Th1/Th2 driven enteritis

Pastorelli

Garg

Hoang

et al. 2010

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362

395

IL-33 is a novel member of the IL-1 family and ligand for the IL-1 receptor-related protein, ST2. Recent evidence suggests that the IL-33/ST2 axis plays a critical role in several autoimmune and inflammatory disorders; however, its role in inflammatory bowel disease (IBD) has not been clearly defined. We characterized IL-33 and ST2 expression and modulation after conventional anti-TNF therapy in Crohn's disease and ulcerative colitis (UC) patients and investigated the role of IL-33 in SAMP1/YitFc (SAMP) mice, a mixed Th1/Th2 model of IBD. Our results showed a specific increase of mucosal IL-33 in active UC, localized primarily to intestinal epithelial cells (IEC) and colonic inflammatory infiltrates. Importantly, increased expression of full-length IL-33, representing the most bioactive form, was detected in UC epithelium, whereas elevated levels of cleaved IL-33 were present in IBD serum. ST2 isoforms were differentially modulated in UC epithelium, and sST2, a soluble decoy receptor with anti-inflammatory properties, was also elevated in IBD serum. Infliximab (anti-TNF) treatment of UC decreased circulating IL-33 and increased sST2, whereas stimulation of HT-29 IEC confirmed IL-33 and sST2 regulation by TNF. Similarly, IL-33 significantly increased and correlated with disease severity, and potently induced IL-5, IL-6, and IL-17 from mucosal immune cells in SAMP mice. Taken together, the IL-33/ST2 system plays an important role in IBD and experimental colitis, is modulated by anti-TNF therapy, and may represent a specific biomarker for active UC.inflammatory bowel disease | anti-TNF therapy | SAMP1/YitFc mouse model