Jerrold R Turner

University of Chicago, Chicago, Illinois, United States

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Publications (201)1828.83 Total impact

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    ABSTRACT: Substance P (SP), neurokinin-1 receptors (NK-1Rs) are expressed in mesenteric preadipocytes and SP binding activates proinflammatory signalling in these cells. We evaluated the expression levels of SP (Tac-1), NK-1R (Tacr-1), and NK-2R (Tacr-2) mRNA in preadipocytes isolated from patients with Inflammatory Bowel Disease (IBD) and examined their responsiveness to SP compared to control human mesenteric preadipocytes. The Aim of our study is to investigate the effects of the neuropeptide SP on cytokine expression in preadipocytes of IBD vs control patients and evaluate the potential effects of these cells on IBD pathophysiology via SP-NK-R interactions.
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    ABSTRACT: Intraepithelial lymphocytes that express the γδ T cell receptor (γδ IELs) limit pathogen translocation across the intestinal epithelium by unknown mechanisms. We investigated whether γδ IEL migration and interaction with epithelial cells promote mucosal barrier maintenance during enteric infection. Salmonella typhimurium or Toxoplasma gondii were administered to γδ T cell-deficient (Tcrd KO), CD103-deficient (CD103 KO), or control TcrdEGFP C57BL/6 reporter mice. Intravital microscopy was used to visualize migration of GFP-tagged γδ T cells within the small intestinal mucosa of mice infected with DsRed-labeled S typhimurium. Mixed bone marrow chimeras were generated to assess the effects of γδ IEL migration on early pathogen invasion and chronic systemic infection. Morphometric analyses of intravital video microscopy data showed that γδ IELs rapidly localized to and remained near epithelial cells in direct contact with bacteria. Within 1 hr, greater numbers of T gondii or S typhimurium were present within mucosae of mice with migration-defective occludin KO γδ T cells, compared with controls. Pathogen invasion in Tcrd KO mice was quantitatively similar to that in mice with occludin-deficient γδ T cells, whereas invasion in CD103 KO mice, which have increased migration of γδ T cells into the lateral intercellular space, was reduced by 63%. Consistent with a role of γδ T cell migration in early host defense, systemic salmonellosis developed more rapidly and with greater severity in mice with occludin-deficient γδ IELs, relative to those with wild-type or CD103 KO γδ IELs. In mice, intraepithelial migration to epithelial cells in contact with pathogens is essential to γδ IEL surveillance and immediate host defense. γδ IEL occludin is required for early surveillance that limits systemic disease. Copyright © 2015 AGA Institute. Published by Elsevier Inc. All rights reserved.
    Gastroenterology 03/2015; DOI:10.1053/j.gastro.2015.02.053 · 12.82 Impact Factor
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    ABSTRACT: In vitro, infection of polarized human intestinal epithelial cells by Coxsackievirus B3 (CVB3) depends on virus interaction with decay accelerating factor (DAF), a receptor expressed on the apical cell surface. Although mice are highly susceptible to CVB3 infection when virus is delivered by intraperitoneal injection, infection by the enteral route is very inefficient. Murine DAF, unlike human DAF, does not bind virus, and we hypothesized that the absence of an accessible receptor on the intestinal surface is an important barrier to infection by the oral route. We generated transgenic mice that express human DAF specifically on intestinal epithelium, and measured their susceptibility to infection by a DAF-binding CVB3 isolate. Human DAF permitted CVB3 to bind to the intestinal surface ex vivo, and to infect polarized monolayers of small-intestinal epithelial cells derived from DAF-transgenic mice. However, expression of human DAF did not facilitate infection by the enteral route, either in immunocompetent animals or in animals deficient in the interferon alpha/beta receptor. These results indicate that the absence of an apical receptor on intestinal epithelium is not the major barrier to infection of mice by the oral route. CVB3 infection of human intestinal epithelial cells depends on DAF at the apical cell surface, and expression of human DAF on murine intestinal epithelial cells permits their infection in vitro. However, expression of human DAF on the intestinal surface of transgenic mice did not facilitate infection by the oral route. Although the role of intestinal DAF in human infection has not been directly examined, these results suggest that DAF is not the critical factor in mice. Copyright © 2015, American Society for Microbiology. All Rights Reserved.
    Journal of Virology 02/2015; DOI:10.1128/JVI.03468-14 · 4.65 Impact Factor
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    ABSTRACT: In Inflammatory Bowel Disease (IBD), obesity is associated with worsening of the course of disease. Here we examined the role obesity in the development of colitis and studied mesenteric fat-epithelial cell interactions in patients with IBD. We combined the diet-induce obesity (DIO) with the Trinitrobenzene Sulfonic Acid (TNBS) colitis mouse model to create groups with obesity, colitis, and their combination. Changes in the mesenteric fat and intestine were assessed by histology, myeloperoxidase (MPO) assay and cytokine mRNA expression by real-time PCR. Medium from human mesenteric fat and cultured preadipocytes was obtained from obese and IBD patients. Histological analysis showed inflammatory cell infiltrate and increased histological damage in the intestine and mesenteric fat of obese mice with colitis compared to all other groups. Obesity also increased the expression of proinflammatory cytokines including IL-1β, TNFα, MCP-1 and KC while it decreased the TNBS-induced increases in IL-2 and IFNγ in mesenteric adipose and intestinal tissues. Human mesenteric fat isolated from obese and IBD patients demonstrated differential release of adipokines and growth factors compared to controls. Fat conditioned media reduced adiponectin receptor 1 (AdipoR1) expression in human NCM460 colonic epithelial cells. AdipoR1 intracolonic silencing in mice exacerbated TNBS-induced colitis. In conclusion, obesity worsens the outcome of experimental colitis and obesity and IBD-associated changes in adipose tissue promote differential mediator release in mesenteric fat that modulate colonocyte responses and may affect the course of colitis. Our results also suggest an important role for AdipoR1 for the fat-intestinal axis in the regulation of inflammation during colitis. Copyright © 2014, American Journal of Physiology- Gastrointestinal and Liver Physiology.
    AJP Gastrointestinal and Liver Physiology 01/2015; DOI:10.1152/ajpgi.00269.2014 · 3.74 Impact Factor
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    ABSTRACT: Tight junctions create a paracellular barrier that is essential for survival of complex organisms. In many cases tight junctions define separate, generally sterile, tissue compartments. In the skin and gut, tight junctions must also seal the paracellular space to prevent microbiota from accessing the internal milieu. This is a relatively simple task in the integument, where an absolute barrier is effective. However, intestinal epithelial tight junctions are charged with the far more complex task of supporting paracellular transport of water, ions, and nutrients while providing a barrier to microbial translocation. The delicate nature of this balance, which is disrupted in disease, makes the intestine a unique organ in which to explore the complexities of tight junction permeability and barrier regulation. Here we review recent progress in understanding the molecular determinants of barrier function and events responsible for regulation, and dysregulation, of tight junction permeability.
    Seminars in Cell and Developmental Biology 09/2014; DOI:10.1016/j.semcdb.2014.09.022 · 5.97 Impact Factor
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    ABSTRACT: Intestinal barrier dysfunction is an important contributor to alcoholic liver disease (ALD). Translocated microbial products trigger an inflammatory response in the liver and contribute to steatohepatitis. Our aim was to investigate mechanisms of barrier disruption after chronic alcohol feeding. A Lieber‐DeCarli model was used to induce intestinal dysbiosis, increased intestinal permeability, and liver disease in mice. Alcohol feeding for 8 weeks induced intestinal inflammation in the jejunum, which is characterized by an increased number of tumor necrosis factor alpha (TNF‐α)‐producing monocytes and macrophages. These findings were confirmed in duodenal biopsies from patients with chronic alcohol abuse. Intestinal decontamination with nonabsorbable antibiotics restored eubiosis, decreased intestinal inflammation and permeability, and reduced ALD in mice. TNF‐receptor I (TNFRI) mutant mice were protected from intestinal barrier dysfunction and ALD. To investigate whether TNFRI on intestinal epithelial cells mediates intestinal barrier dysfunction and ALD, we used TNFRI mutant mice carrying a conditional gain‐of‐function allele for this receptor. Reactivation of TNFRI on intestinal epithelial cells resulted in increased intestinal permeability and liver disease that is similar to wild‐type mice after alcohol feeding, suggesting that enteric TNFRI promotes intestinal barrier dysfunction. Myosin light‐chain kinase (MLCK) is a downstream target of TNF‐α and was phosphorylated in intestinal epithelial cells after alcohol administration. Using MLCK‐deficient mice, we further demonstrate a partial contribution of MLCK to intestinal barrier dysfunction and liver disease after chronic alcohol feeding. Conclusion: Dysbiosis‐induced intestinal inflammation and TNFRI signaling in intestinal epithelial cells mediate a disruption of the intestinal barrier. Therefore, intestinal TNFRI is a crucial mediator of ALD. (Hepatology 2015;61:883–894)
    Hepatology 09/2014; 61(3). DOI:10.1002/hep.27489 · 11.19 Impact Factor
  • Gastrointestinal Endoscopy 09/2014; 80(3):516–517. DOI:10.1016/j.gie.2014.07.022 · 4.90 Impact Factor
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    ABSTRACT: Approximately half of all adult burn patients are intoxicated at the time of their injury and have worsened clinical outcomes compared to those without prior alcohol exposure. This study tested the hypothesis that intoxication alters the gut-liver axis leading to increased pulmonary inflammation mediated by burn-induced IL-6 in the liver. To this end, C57BL/6 mice were given 1.2 g/kg ethanol 30 minutes prior to a 15% total body surface area burn. To restore gut barrier function, a specific myosin light chain kinase inhibitor [membrane-permeant inhibitor of kinase (PIK)] was administered 30 minutes after injury which we have demonstrated to reduce bacterial translocation from the gut. Limiting bacterial translocation with PIK attenuated hepatic damage as measured by a 47% reduction in serum alanine aminotransferase (p<0.05) as well as a 33% reduction in hepatic IL-6 mRNA expression (p<0.05) compared to intoxicated burned mice without PIK. This mitigation of hepatic damage was associated with a 49% decline in pulmonary neutrophil infiltration (p<0.05) and decreased alveolar wall thickening compared to matched controls. These results were reproduced by prophylactically reducing the bacterial load in the intestines with oral antibiotics before intoxication and burn. Overall these data suggest the gut-liver axis is deranged when intoxication precedes burn and that limiting bacterial translocation in this setting attenuates hepatic damage and pulmonary inflammation.
    AJP Gastrointestinal and Liver Physiology 08/2014; 307(7). DOI:10.1152/ajpgi.00185.2014 · 3.74 Impact Factor
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    ABSTRACT: Previous studies have shown a correlation between pretransplant conditioning intensity, intestinal barrier loss, and graft-versus-host disease (GVHD) severity. However, because irradiation and other forms of pretransplant conditioning have pleiotropic effects, the precise role of intestinal barrier loss in GVHD pathogenesis remains unclear. We developed GVHD models that allowed us to isolate the specific contributions of distinct pretransplant variables. Intestinal damage was required for the induction of minor mismatch [major histocompatibility complex (MHC)-matched] GVHD, but was not necessary for major mismatch GVHD, demonstrating fundamental pathogenic distinctions between these forms of disease. Moreover, recipient natural killer (NK) cells prevented minor mismatch GVHD by limiting expansion and target organ infiltration of alloreactive T cells via a perforin-dependent mechanism, revealing an immunoregulatory function of MHC-matched recipient NK cells in GVHD. Minor mismatch GVHD required MyD88-mediated Toll-like receptor 4 (TLR4) signaling on donor cells, and intestinal damage could be bypassed by parenteral lipopolysaccharide (LPS) administration, indicating a critical role for the influx of bacterial components triggered by intestinal barrier loss. In all, the data demonstrate that pretransplant conditioning plays a dual role in promoting minor mismatch GVHD by both depleting recipient NK cells and inducing intestinal barrier loss.
    Science translational medicine 07/2014; 6(243):243ra87. DOI:10.1126/scitranslmed.3008941 · 14.41 Impact Factor
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    ABSTRACT: Abnormal bacterial adherence and internalization in enterocytes have been documented in Crohn disease, celiac disease, surgical stress, and intestinal obstruction and are associated with low-level interferon (IFN)-γ production. How commensals gain access to epithelial soma through densely packed microvilli rooted on the terminal web (TW) remains unclear. We investigated molecular and ultrastructural mechanisms of bacterial endocytosis, focusing on regulatory roles of IFN-γ and myosin light chain kinase (MLCK) in TW myosin phosphorylation and brush border fanning. Mouse intestines were sham operated on or obstructed for 6 hours by loop ligation with intraluminally administered ML-7 (a MLCK inhibitor) or Y27632 (a Rho-associated kinase inhibitor). After intestinal obstruction, epithelial endocytosis and extraintestinal translocation of bacteria were observed in the absence of tight junctional damage. Enhanced TW myosin light chain phosphorylation, arc formation, and brush border fanning coincided with intermicrovillous bacterial penetration, which were inhibited by ML-7 and neutralizing anti-IFN-γ but not Y27632. The phenomena were not seen in mice genetically deficient for long MLCK-210 or IFN-γ. Stimulation of human Caco-2BBe cells with IFN-γ caused MLCK-dependent TW arc formation and brush border fanning, which preceded caveolin-mediated bacterial internalization through cholesterol-rich lipid rafts. In conclusion, epithelial MLCK-activated brush border fanning by IFN-γ promotes adherence and internalization of normally noninvasive enteric bacteria. Transcytotic commensal penetration may contribute to initiation or relapse of chronic inflammation.
    American Journal Of Pathology 06/2014; 184(8). DOI:10.1016/j.ajpath.2014.05.003 · 4.60 Impact Factor
  • Digestive disease week, Chicago; 05/2014
  • Gastroenterology 05/2014; 146(5):S-80. DOI:10.1016/S0016-5085(14)60288-2 · 13.93 Impact Factor
  • Gastroenterology 05/2014; 146(5):S-521. DOI:10.1016/S0016-5085(14)61887-4 · 13.93 Impact Factor
  • Matthew A. Odenwald, Aaron L. Hecht, Jerrold R. Turner
    Gastroenterology 05/2014; 146(5):S-36. DOI:10.1016/S0016-5085(14)60125-6 · 13.93 Impact Factor
  • Gastroenterology 05/2014; 146(5):S-823. DOI:10.1016/S0016-5085(14)62986-3 · 13.93 Impact Factor
  • Gastroenterology 05/2014; 146(5):S-73. DOI:10.1016/S0016-5085(14)60263-8 · 13.93 Impact Factor
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    Gastroenterology 05/2014; 146(5):S783-4. DOI:10.1016/S0016-5085(14)62827-4 · 12.82 Impact Factor
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    ABSTRACT: Sterol Response Element Binding Protein 2 (SREBP2) transcription factor is a master regulator of cholesterol homeostasis. Treatment with statins, inhibitors of cholesterol synthesis, activates intestinal SREBP2, which may hinder their cholesterol-lowering effects. Overactivation of SREBP2 in mouse liver was shown to have no effect on plasma cholesterol. However, the influence of activating intestinal SREBP2 on plasma cholesterol is not known. We have generated a novel transgenic mouse model with intestine specific overexpression of active SREBP2 (ISR2) driven by villin promoter. ISR2 mice showed overexpression of active SREBP2 specifically in the intestine. Microarray analysis of jejunal RNA from ISR2 mice showed a significant increase in genes involved in fatty acid and cholesterol synthesis. Cholesterol and triglyceride (TG) in jejunum and liver (mg/g protein) were significantly increased in ISR2 vs wild type mice. Serum Cholesterol was significantly increased in VLDL and LDL fractions whereas the level of serum triglycerides was decreased in ISR2 vs wild type mice. In conclusion, activation of intestinal SREBP2 alone seems to be sufficient to increase plasma cholesterol, highlighting the essential role of intestine in maintaining cholesterol homeostasis in the body.
    PLoS ONE 01/2014; 9(1):e84221. DOI:10.1371/journal.pone.0084221 · 3.53 Impact Factor
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    ABSTRACT: In vitro and in vivo studies have implicated occludin in regulation of paracellular macromolecular flux at steady-state and in response to tumor necrosis factor (TNF). To define the roles of occludin in these processes, intestinal epithelia with stable occludin knockdown were established. Knockdown monolayers had markedly enhanced tight junction permeability to large molecules that could be modeled by size-selective channels with radii of ∼62.5Å. TNF increased paracellular flux of large molecules in occludin-sufficient, but not occludin-deficient, monolayers. Complementation using full length or C-terminal OCEL domain-deficient EGFP-occludin showed that TNF-induced occludin endocytosis and barrier regulation both required the OCEL domain. Either TNF treatment or OCEL deletion accelerated EGFP-occludin fluorescent recovery, but TNF treatment did not affect behavior of EGFP- occludin(ΔOCEL). Further, the free OCEL domain prevented TNF-induced acceleration of occludin fluorescent recovery, occludin endocytosis, and barrier loss. OCEL mutated within a recently-proposed ZO-1 binding domain (K433) could not inhibit TNF effects, but OCEL mutated within the ZO-1 SH3-GuK binding region (K485/K488) remained functional. We conclude that OCEL-mediated occludin interactions are essential for limiting paracellular macromolecular flux. Moreover, our data implicate interactions mediated by the OCEL K433 region as an effector of TNF-induced barrier regulation.
    Molecular biology of the cell 08/2013; DOI:10.1091/mbc.E12-09-0688 · 5.98 Impact Factor
  • Emily S Turner, Jerrold R Turner
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    ABSTRACT: See "Identification of molecular subtypes of gastric cancer with different responses to PI3-kinase inhibitors and 5-fluorouracil," by Lei Z, Tan IB, Das K, et al, on page 000. Q1 A denocarcinoma of the stomach remains a major public health issue. Although the incidence of this cancer in the United States has been falling, with only 21,600 new cases expected in 2013, 1 the prognosis for patients remains grim. Despite improvements in treat-ment approaches, 5-year survival remains at <30%. 1 In addition to the typically advanced stage of diagnosis for most gastric adenocarcinomas, these dismal survival sta-tistics reflect the lack of effective treatment options. Identifying specific signaling pathways in individual pa-tients might improve treatment outcomes, but only limited data are available. In this issue of GASTROENTER-OLOGY, Lei et al 2 describe 1 approach to overcoming this obstacle. Their results identify 3 molecular signatures of gastric adenocarcinoma (Table 1). Patient survival data indicate that one of these subtypes may best be treated using 5-fluorouracil. In vitro data also suggest that another subtype may be particularly sensitive to phos-phatidyl-inositol-3-kinase inhibitors. This study builds on previous mRNA analyses of gastric cancers by this group and others. 3–10 By combining 192 previously reported 9 and 56 new microarray expression profiles, Lei et al 2 created a database describing 248 Sin-gaporean primary gastric cancers. These were broken into 3 unique groups using hierarchical clustering with itera-tive feature selection. The 201 gastric cancers that best represented the 3 groups were used to develop classifica-tion algorithms. The algorithms were then validated using a separate set of 70 Australian primary gastric cancers. Thus, at least for gastric cancers arising in Singapore and Australia, subclassification into the 3 groups is reproducible. To better understand the biological significance of the distinct groups, Lei et al 2 examined the differentially expressed genes. The clusters were designated as mesen-chymal, to reflect expression of genes in the epithelial-mesenchymal transition pathway; proliferative, because growth promoting oncogenic pathways were activated; and metabolic, owing to expression of genes associated with metabolic pathways. Further analyses of each group showed that mesen-chymal tumors lost expression of E-cadherin, the epithe-lial cadherin isoform. Consistent with the frequent loss of E-cadherin expression in signet ring cell gastric cancers, nearly 60% of mesenchymal tumors were classified as Lauren's diffuse type (Figure 1A), and 70% had at least some features of diffuse gastric cancer. 11 Further, consis-tent with reports that diffuse gastric cancers tend to be hypermethylated, 12 mesenchymal tumors displayed genomic hypermethylation. Transforming growth factor-b, vascular endothelial growth factor, nuclear factor-kB, mammalian target of rapamycin, sonic hedgehog, and stem cancer stem cell pathways were also activated in mesenchymal gastric cancers. In contrast, p53 mutations and DNA copy number variations were limited. In contrast with mesenchymal gastric adenocarcinomas, nearly 75% of proliferative tumors were Lauren's intestinal type (Figure 1B). These tumors tended to have activation of E2F, MYC, and RAS pathways and mutations of CCNE1, MYC, ERBB2, and KRAS. Proliferative cancers were hypomethylated and often harbored p53 mutations. These characteristics suggest that the proliferative cluster over-laps with Lauren's intestinal type and that this group includes tumors responsive to therapies targeting endo-thelial growth factor receptor (EGFR) Q2
    Gastroenterology 07/2013; 145(3). DOI:10.1053/j.gastro.2013.07.019 · 12.82 Impact Factor

Publication Stats

7k Citations
1,828.83 Total Impact Points


  • 2002–2015
    • University of Chicago
      • Department of Pathology
      Chicago, Illinois, United States
  • 2011–2013
    • The University of Chicago Medical Center
      • Department of Pathology
      Chicago, Illinois, United States
  • 2005–2013
    • University of Illinois at Chicago
      Chicago, Illinois, United States
    • Johns Hopkins University
      Baltimore, Maryland, United States
    • The University of Calgary
      • Department of Biological Sciences
      Calgary, Alberta, Canada
  • 2012
    • Medical College of Wisconsin
      • Department of Microbiology and Molecular Genetics
      Milwaukee, WI, United States
  • 2009
    • University of Pittsburgh
      • Department of Cell Biology and Physiology
      Pittsburgh, Pennsylvania, United States
    • University of Tuebingen
      Tübingen, Baden-Württemberg, Germany
  • 2007
    • Harvard University
      Cambridge, Massachusetts, United States
  • 2000–2001
    • Wayne State University
      • Department of Pathology
      Detroit, MI, United States