Andrew Gewirtz

..Conclusion Regardless of whether they harbour a colitogenic microbiota, loss of TLR5 predisposes mice to colitis triggered by immune dysregulation via an IL-1β-dependent pathway...

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..These data suggest that LXA4 and its stable analogs may be useful in downregulating active inflammation at mucosal surfaces...

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..Lipoxin analogs could be potentially useful for a wide array of disease states that have an inflammatory component, and look particularly promising for treatment of inflammatory bowel disease...

..This minireview considers the current findings regarding TLR expression in the intestinal epithelium and the role these receptors might serve in host defense...

..By March 2002, tacrolimus had entered phase III trials for inflammatory bowel disease (IBD) in Japan [442503]. This evaluation will focus on the development of tacrolimus for this indication...

..Isis is developing alicaforsen, an RNase H-dependent antisense inhibitor of intercellular adhesion molecule-1, for the potential treatment of ulcerative colitis. The therapy is currently undergoing phase II clinical trials...

..These results demonstrate that natural acquisition of immune responses to flagellin are regulated by TLR5 and suggest that immune responses to flagellin are not merely associated with CD but rather promote the pathogenic response...

..Thus, LXA(4) analog-mediated down-regulation of proinflammatory gene expression via inhibition of the NF-kappaB pathway can be therapeutic for diseases characterized by mucosal inflammation...

..US-05514788, and other patents, cover antisense cell adhesion molecule inhibitors [212289], [234792]...

..These findings indicate that translocation of flagellin across epithelia, subsequent to apical epithelial-S. typhimurium interaction, is likely a major means of activating a mucosal inflammatory response...

..Thus the cellular basis of action of these natural off-switches to inflammation appears to involve downregulation of neutrophil azurophilic granule release...

..This article discusses the evidence that supports a role for flagellin in Crohn's disease and considers the potential roles of these responses in the pathophysiology of this disorder...

..We have previously shown that A(2B)AR mRNA and protein levels are up-regulated during colitis. In this study, we addressed the role of the A(2B)AR in the development of murine colitis and the potential mechanism underlying its effects...

..All together, these results indicate that the resistance of TLR5KO mice to Salmonella-induced typhoid-like illness resulted from alterations in their basal phenotype rather than from the lack of TLR5 ligation during the infection per se...

..Thus LXA(4) generated in or near the paracellular space via neutrophil-epithelial interactions can rapidly act on epithelial LXA(4)R to downregulate epithelial promotion of intestinal inflammation...

..That an engineered innate immune deficiency ultimately results in spontaneous intestinal inflammation supports the notion that an innate immune deficiency might underlie some instances of inflammatory bowel disease...

..Together, these results indicate that epithelial TLR5 mediates p38 activation and subsequently regulates flagellin-induced IL-8 expression independently of NF-kappaB, probably by influencing IL-8 mRNA translation...

..These observations provide evidence for an intraluminal biological signaling of leptin and a new pathophysiological role for intraluminal leptin during states of intestinal inflammation such as inflammatory bowel disease...

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..Thus inhibition of MMP-9 may be beneficial in treatment of colitis even if resulting in inhibition of MMP-2...

..Thus, systemic administration of flagellin may be a relatively safe means of providing temporary non-specific protection against a variety of challenges...

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..Such intertwining of proinflammatory and apoptotic signaling mediated by bacterial products suggests roles for host programmed cell death in the pathogenesis of enteric infections...

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..The intracellular accumulation of such di-tripeptides may be important in enterocytes becoming immune accessory cells...

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..Together, our data suggest that a critical balance between the two gelatinases determines the outcome of inflammatory response during acute colitis...

..Thus, acquisition of a humoral immune response to flagellin requires activation of innate immunity, is T cell dependent, and can originate from flagellin in the intestinal tract in inflammatory conditions in the intestine...

..Neurogenic inflammation plays a major role in the pathogenesis of inflammatory bowel disease (IBD). We examined the role of neuropeptide Y (NPY) and neuronal nitric oxide synthase (nNOS) in modulating colitis...

..These indexes of gut barrier dysfunction are ameliorated or blunted by administration of dietary GLN or oral ABX, respectively. Dietary GLN upregulates small bowel sIgA in this model...

..These data may have mechanistic and therapeutic implications in diseases such as IBD and rheumatoid arthritis in which IL-6 plays an important role in the pathogenesis...

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..pylori flagellin plays no role in activating epithelial orchestration of inflammation. We conclude that H. pylori evades TLR5-mediated detection, which may contribute to its long-term persistence in individual hosts...

..This notion is consistent with the emerging paradigm that specific TLR ligands may have a fundamental cytoprotective effect during inflammatory stress...

..typhimurium-induced proinflammatory responses through basolateral TLR5 and is consistent with the emerging model of S. typhimurium flagellin-induced inflammation...

..These results support the concept that increased susceptibility to infections and poor adaptive immune responses in aging may be due to the decline in TLR expression and function...

..We conclude that adults with PN-dependent SBS are systemically exposed to flagellin and LPS, presumably from the gut lumen. This likely regulates innate and adaptive immune responses to these specific bacterial products...

..This article reviews studies performed in vitro, in mice, and in humans that indicate an important role for the flagellin-TLR5 interaction in regulating both the innate and adaptive immune responses in the intestine...

..These results suggest that extracellular ATP plays an essential role in the TCR-mediated signal transduction cascade for expression of certain cytokine genes...

..Collectively, these data demonstrate that TNF-alpha-induced A(2B)AR expression in colonic epithelial cells is post-transcriptionally regulated by miR27b and miR128a and show that miR27b influences A(2B)AR expression in murine colitis...

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..Thus, the characteristic inflammatory pathology of Salmonella infection occurs only in PPs and to a lesser extent in MLN during the initial phases of infection and these early responses are dependent on TLR5...

..In April 2003, preclinical and early clinical studies were underway for a variety of indications, including congestive heart failure and pancreatitis...

..Altogether these findings point to ADAM-15 as a possible therapeutic target for prevention of inappropriate T cell activation involved in some pathologies...

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..Thus, TLR5's rapid activation of PI3K serves to limit MAPK signaling, thus limiting proinflammatory gene expression and reducing the potential negative consequences of proinflammatory gene expression...

..Thus, it should be possible to design innate immune activators that are highly effective vaccine adjuvants yet avoid the adverse events associated with systemic TLR activation...

..Thus, underlying CMV infection can alter mucosal immunity, potentially increasing the tendency of CMV-infected hosts to develop colitis...

..FN may be a critical host factor that modulates adherence and invasion of bacteria, thus playing a key role in mucosal immune responses during inflammation...

..In this study, we sought to address the role and mechanism by which MMP-9 influences barrier protective function...

..Together, these results indicate that epithelial cell induction of flagellin-specific gene expression is mediated, in part, by STAT activation that results from autocrine activation via IL-6...

..Thus, S. typhimurium flagellin is the major molecular trigger by which this pathogen activates gut epithelial proinflammatory gene expression...

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..Our data provide a novel mechanism by which events such as adhesion may be integrated by amino acid transport activity resulting from the direct interaction of cell surface molecules such as CD98 and ICAM-1...

..Thus, in vivo both radioresistant and hemopoietic cells play key nonredundant roles in mediating innate and adaptive immune responses to flagellin...

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..Such immune changes might be a common mechanism for the myriad negative health effects of shift work...

..These results support the emerging view that the gut microbiota contributes to metabolic disease and suggest that malfunction of the innate immune system may promote the development of metabolic syndrome...

..Thus, depending on the original danger signal, vascular DCs edit the emerging immune response by differentially recruiting specialized T effector cells and direct the disease process toward distinct types of vasculitis...

..This article reviews such progress and discusses these challenges in the context of focusing on 1 particular protein, bacterial flagellin...

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..These results show that selective cryptdins may amplify their roles in innate immunity by acting as novel paracrine agonists to coordinate an inflammatory response with the antimicrobial secretions of Paneth cells...

..MOLF-Ity mice, they exhibit a different phenotype with respect to Tlr5 expression and Tlr5 signaling, supporting the prediction that Tlr5 is not primarily involved in the disease phenotype underlying the Ity3 locus in MOLF/Ei mice...

..We conclude that MUC1/Muc1 suppresses pulmonary innate immunity and speculate its anti-inflammatory activity may play an important modulatory role during microbial infection...

..This observation may explain, in part, the observed reactogenicity of cholera vaccine strains in humans...

..Such an adjuvant effect for flagellin has important implications for vaccine development and the generation of CD4 T cell responses to enteric bacteria...

..We expect this information will prove insightful toward understanding the pathogenesis of Crohn's disease and ulcerative colitis, collectively referred to as inflammatory bowel disease. ..

..Thus, we propose to understand the role of the interaction in mouse models of disease. ..

..In addition to containing an extensive array of basic research equipment, this lab space contains a new thermostatted spectrofluorimeter to be used primarily by Dr. Gewirtz. ..

..Thus, we propose to understand the role of the interaction in mouse models of disease. ..

..PUBLIC HEALTH RELEVANCE: The overall goal of this application is to leverage our ongoing studies on flagellin-induced gut epithelial chemokine secretion to begin to develop a new paradigm of protection against pandemic infection. ..

..In vitro and in vivo models will be utilized. ..