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1.
J Prev Alzheimers Dis ; 9(4): 646-654, 2022.
Article in English | MEDLINE | ID: mdl-36281668

ABSTRACT

BACKGROUND: Cognitive reserve has been hypothesized as a mechanism to explain differences in individual risk for symptomatic expression of Alzheimer's Disease (AD). Inappropriate medications may diminish cognitive reserve, precipitating the transition from preclinical AD (pAD) to a symptomatic state. To date, there is limited data on the potential impact of medication optimization as a potential tool for slowing the symptomatic expression of AD. OBJECTIVES: (1) To test the efficacy of a medication therapy management intervention designed to bolster cognitive reserve in community-dwelling older adults without dementia. (2) To evaluate the efficacy of intervention by baseline pAD status. DESIGN: A 1-year randomized controlled trial was conducted in community-dwelling older adults without dementia. Randomization was stratified by amyloid ß positron emission tomography levels. SETTING: Community-based, Lexington, Kentucky. PARTICIPANTS: Adults 65 years or older with no evidence of dementia and reporting at least one potentially inappropriate medication as listed in the Beers 2015 criteria were recruited. The study aimed to enroll 90 participants based on the a priori sample size calculation. INTERVENTION: Medication therapy management versus standard of care. MEASUREMENTS: Primary outcomes were: (1) one-year changes in the Medication Appropriateness Index; (2) one-year changes in Trail Making Test B under scopolamine challenge. RESULTS: The medication therapy management intervention resulted in significant improvement in Medication Appropriateness Index scores. Overall, there was no beneficial effect of the medication therapy management on Trail Making Test B scores, however stratified analysis demonstrated improvement in Trail Making Test B challenged scores associated with the medication therapy management for those with elevated amyloid ß positron emission tomography levels consistent with pAD. CONCLUSIONS: Medication therapy management can reduce inappropriate medication use in older adults at risk for AD. Our study indicated beneficial cognitive effects in those with preclinical Alzheimer's Disease. No statistically significant effects were evident in the study group as a whole, or in those without preclinical cerebral amyloidosis. Further work designed to improve the effectiveness of the medication therapy management approach and defining other preclinical pathologic states that may benefit from medication optimization are readily achievable goals for promoting improved cognitive health and potentially delaying the onset of symptomatic AD.


Subject(s)
Alzheimer Disease , Cognitive Reserve , Humans , Aged , Alzheimer Disease/metabolism , Amyloid beta-Peptides/metabolism , Medication Therapy Management , Prodromal Symptoms , Scopolamine Derivatives/therapeutic use
2.
Expert Rev Clin Pharmacol ; 10(11): 1239-1250, 2017 Nov.
Article in English | MEDLINE | ID: mdl-28766951

ABSTRACT

INTRODUCTION: Infections with Clostridium difficile (CDI) represent a major burden for the health care system. Treatment is generally by antibiotic therapy with metronidazole and vancomycin, but efficacy remains suboptimal. Areas covered: This review discusses established and emerging treatment options for CDI, and current therapeutic guidelines, taking into account disease severity and risk of relapse. Expert commentary: New therapeutic approaches, including antibodies and new classes of antibiotics, and new measures for preventing infection with vaccines are under development in phase II/III clinical trials. We performed a systematic literature review using the search terms 'Clostridium difficile' and 'treatment'.


Subject(s)
Anti-Bacterial Agents/therapeutic use , Clostridioides difficile/isolation & purification , Clostridium Infections/drug therapy , Animals , Clostridium Infections/microbiology , Drug Design , Humans , Metronidazole/therapeutic use , Practice Guidelines as Topic , Recurrence , Severity of Illness Index , Vancomycin/therapeutic use
3.
Eur J Med Chem ; 120: 353-62, 2016 Sep 14.
Article in English | MEDLINE | ID: mdl-27236016

ABSTRACT

Diarrhoeal diseases caused by the intestinal parasites Giardia lamblia and Entamoeba histolytica constitute a major global health burden. Nitroimidazoles are first-line drugs for the treatment of giardiasis and amebiasis, with metronidazole 1 being the most commonly used drug worldwide. However, treatment failures in giardiasis occur in up to 20% of cases and development of resistance to metronidazole is of concern. We have re-examined 'old' nitroimidazoles as a foundation for the systematic development of next-generation derivatives. Using this approach, derivatisation of the nitroimidazole carboxamide scaffold provided improved antiparasitic agents. Thirty-three novel nitroimidazole carboxamides were synthesised and evaluated for activity against G. lamblia and E. histolytica. Several of the new compounds exhibited potent activity against G. lamblia strains, including metronidazole-resistant strains of G. lamblia (EC50 = 0.1-2.5 µM cf. metronidazole EC50 = 6.1-18 µM). Other compounds showed improved activity against E. histolytica (EC50 = 1.7-5.1 µM cf. metronidazole EC50 = 5.0 µM), potent activity against Trichomonas vaginalis (EC50 = 0.6-1.4 µM cf. metronidazole EC50 = 0.8 µM) and moderate activity against the intestinal bacterial pathogen Clostridium difficile (0.5-2 µg/mL, cf. metronidazole = 0.5 µg/mL). The new compounds had low toxicity against mammalian kidney and liver cells (CC50 > 100 µM), and selected antiparasitic hits were assessed for human plasma protein binding and metabolic stability in liver microsomes to demonstrate their therapeutic potential.


Subject(s)
Antiparasitic Agents/pharmacology , Nitroimidazoles/pharmacology , Parasites/drug effects , Animals , Cells, Cultured , Drug Resistance , Drug Stability , Entamoeba histolytica/drug effects , Giardia lamblia/drug effects , Humans , Trichomonas vaginalis/drug effects
5.
Aliment Pharmacol Ther ; 40(5): 477-85, 2014 Sep.
Article in English | MEDLINE | ID: mdl-25041724

ABSTRACT

BACKGROUND: Accurate and reproducible measurement of expression of pro-inflammatory cytokines in colonic biopsies from patients with ulcerative colitis (UC) is essential for proof-of-concept and mechanism-of-action studies. Few studies have rigorously established the number of biopsies required for accurate and reproducible biomarker measurements. AIM: To validate methods for measuring changes in gene expression in colonic biopsy samples. METHODS: Twelve colonic biopsies were obtained from each of six healthy controls, six patients with inactive UC and seven patients with active UC. Mayo endoscopic scores were used as a clinical reference standard. Quantitative PCR was used to assess mRNA expression of eight known inflammatory genes. The power to detect a reduction in gene expression in active vs. inactive UC was calculated using a linear mixed effect model. RESULTS: mRNA analysis of colonic biopsies is a sensitive and feasible approach for measuring inflammatory gene expression in colonic biopsies. Inflammatory biomarkers correlate with Mayo endoscopic subscores for each colonic region. For most genes, three rectal biopsies from two to four patients are required to detect changes in gene expression corresponding to active vs. inactive UC to achieve a power of 80% with an alpha of 0.05. CONCLUSION: Our data suggest that systematic measurement of inflammatory biomarkers at the mRNA level can be a valuable tool for hypothesis testing, and assessment of clinical activity and response to therapy in ulcerative colitis.


Subject(s)
Colitis, Ulcerative/genetics , Cytokines/genetics , Gene Expression Regulation , Adult , Aged , Biomarkers/analysis , Biopsy , Clinical Trials as Topic , Colitis, Ulcerative/pathology , Colon/metabolism , Colon/pathology , Female , Humans , Male , Middle Aged , RNA, Messenger/metabolism
6.
Mucosal Immunol ; 7(1): 134-42, 2014 Jan.
Article in English | MEDLINE | ID: mdl-23695512

ABSTRACT

Intraepithelial γδ T lymphocytes (γδ IEL) have important roles in repair of tissue damage at epithelial sites, such as skin and intestine. Molecules that orchestrate these γδ T-cell functions are not well defined. Recently, interaction of the semaphorin CD100 on skin γδ T cells with plexin B2 on keratinocytes was shown to be important for effective γδ T-cell function in the epidermis, which raised the possibility that CD100 may exert similar functions in the intestinal tract. In this study, we find that CD100 is expressed on all IEL, and plexin B2 is present on all epithelial cells of the mouse colon. Using the dextran sulfate sodium (DSS) mouse model of colitis, disease severity is significantly exacerbated in CD100-deficient (CD100(-/-)) mice, with increased colon ulceration and mucosal infiltration with inflammatory cells. The severe colitis in CD100(-/-) mice is attributable to the failure of the colon epithelium to mount a proliferative response to damage. Unlike wild-type γδ IEL, γδ IEL from CD100(-/-) mice fail to produce keratinocyte growth factor-1 (KGF-1) in response to DSS treatment. Administration of recombinant KGF-1 to CD100(-/-) animals ameliorates disease and reverses colitis susceptibility. These results demonstrate that CD100-mediated signals are critical for effective activation of γδ IEL to produce growth factors, including KGF-1, that are required for healing of the colon epithelium during colitis.


Subject(s)
Antigens, CD/metabolism , Colitis/immunology , Colitis/metabolism , Receptors, Antigen, T-Cell, gamma-delta/metabolism , Semaphorins/metabolism , T-Lymphocytes/immunology , T-Lymphocytes/metabolism , Animals , Antigens, CD/genetics , Colitis/chemically induced , Colitis/genetics , Colitis/pathology , Dextran Sulfate/adverse effects , Disease Models, Animal , Female , Fibroblast Growth Factor 7/metabolism , Gene Expression , Genetic Predisposition to Disease , Intestinal Mucosa/cytology , Intestinal Mucosa/immunology , Intestinal Mucosa/metabolism , Intestinal Mucosa/pathology , Mice , Mice, Knockout , Nerve Tissue Proteins/genetics , Nerve Tissue Proteins/metabolism , Semaphorins/genetics
7.
Clinical and vaccine immunology ; 18(11): 1823-1833, Nov.2011.
Article in English | Sec. Est. Saúde SP, SESSP-IBPROD, Sec. Est. Saúde SP, SESSP-IBACERVO | ID: biblio-1062096

ABSTRACT

countries. Intimate adhesion of the bacteria to intestinal cells occurs via binding of the adhesin intimin to theTIR receptor exposed on cell surfaces. Here, Lactobacillus casei expressing a fragment of -intimin (L.casei-Intcv) was tested as mucosal vaccines in mice against intestinal colonization with the murine pathogenCitrobacter rodentium. Oral or sublingual immunization of C57BL/6 mice with L. casei-Intcv induced anti-IntcvIgA in feces but no IgG in sera. Conversely, anti-Intcv IgG was induced in the sera of mice after sublingualimmunization with purified Intcv. All vaccines were able to decrease C. rodentium recovery from feces. However,this reduction was more evident and sustained over time in mice immunized with L. casei-Intcv by thesublingual route. These mice also displayed an increase in interleukin 6 (IL-6) and gamma interferon (IFN- )secretion by spleen cells 10 days after infection. Additionally, oral or sublingual immunization of C3H/HePasmice, which are highly susceptible to C. rodentium infection, with L. casei-Intcv induced anti-Intcv antibodiesand significantly increased survival after challenge. Immunohistological analysis of colon sections revealedthat C. rodentium was located in deep fractions of the tissue from C3H/HePas mice immunized with L. casei whereas superficial staining was observed in colon sections from mice immunized with L. casei-Intcv. The results indicate that vaccines composed of L. casei expressing intimin may represent a promising approach and that the C3H/HePas infection model with C. rodentium can be used to evaluate potential vaccines against EPEC.


Subject(s)
Rats , Administration, Oral , Administration, Sublingual , Interferon-gamma , Spleen/anatomy & histology , Spleen/immunology , Citrobacter rodentium/pathogenicity , Lacticaseibacillus casei/genetics
8.
Clin Vaccine Immunol ; 18(11): 1823-33, 2011 Nov.
Article in English | MEDLINE | ID: mdl-21900533

ABSTRACT

Enteropathogenic Escherichia coli (EPEC) is a common cause of diarrhea in children from developing countries. Intimate adhesion of the bacteria to intestinal cells occurs via binding of the adhesin intimin to the TIR receptor exposed on cell surfaces. Here, Lactobacillus casei expressing a fragment of ß-intimin (L. casei-Int(cv)) was tested as mucosal vaccines in mice against intestinal colonization with the murine pathogen Citrobacter rodentium. Oral or sublingual immunization of C57BL/6 mice with L. casei-Int(cv) induced anti-Int(cv) IgA in feces but no IgG in sera. Conversely, anti-Int(cv) IgG was induced in the sera of mice after sublingual immunization with purified Int(cv). All vaccines were able to decrease C. rodentium recovery from feces. However, this reduction was more evident and sustained over time in mice immunized with L. casei-Int(cv) by the sublingual route. These mice also displayed an increase in interleukin 6 (IL-6) and gamma interferon (IFN-γ) secretion by spleen cells 10 days after infection. Additionally, oral or sublingual immunization of C3H/HePas mice, which are highly susceptible to C. rodentium infection, with L. casei-Int(cv) induced anti-Int(cv) antibodies and significantly increased survival after challenge. Immunohistological analysis of colon sections revealed that C. rodentium was located in deep fractions of the tissue from C3H/HePas mice immunized with L. casei whereas superficial staining was observed in colon sections from mice immunized with L. casei-Int(cv.) The results indicate that vaccines composed of L. casei expressing intimin may represent a promising approach and that the C3H/HePas infection model with C. rodentium can be used to evaluate potential vaccines against EPEC.


Subject(s)
Adhesins, Bacterial/immunology , Bacterial Vaccines/immunology , Citrobacter rodentium/immunology , Drug Carriers , Enterobacteriaceae Infections/prevention & control , Escherichia coli Proteins/immunology , Genetic Vectors , Lacticaseibacillus casei/genetics , Adhesins, Bacterial/genetics , Administration, Oral , Administration, Sublingual , Animals , Antibodies, Bacterial/blood , Bacterial Vaccines/administration & dosage , Citrobacter rodentium/genetics , Colon/pathology , Enterobacteriaceae Infections/immunology , Enterobacteriaceae Infections/microbiology , Enterobacteriaceae Infections/mortality , Escherichia coli Proteins/genetics , Feces/microbiology , Female , Humans , Immunization/methods , Interferon-gamma/metabolism , Interleukin-6/metabolism , Leukocytes, Mononuclear/immunology , Mice , Mice, Inbred C3H , Mice, Inbred C57BL , Spleen/immunology , Survival Analysis , Vaccines, Synthetic/administration & dosage , Vaccines, Synthetic/immunology
10.
Infect Immun ; 71(9): 5394-7, 2003 Sep.
Article in English | MEDLINE | ID: mdl-12933891

ABSTRACT

Trypanosoma cruzi metacyclic trypomastigotes (MT), but not blood form trypomastigotes (BFT), are highly mucosally infective. We investigated the abilities of MT and BFT to induce inflammation and/or intracellular killing activity within mucosal epithelia. BFT, but not MT, induced marked increases in interleukin-8, GRO-alpha, MCP-1, and nitric oxide production in HeLa and AGS cells, despite similar infectivities. MT may avoid induction of inflammation as an important biological mechanism facilitating mucosal invasion.


Subject(s)
Chemokines, CXC , Interleukin-8/biosynthesis , Nitric Oxide/biosynthesis , Trypanosoma cruzi/pathogenicity , Animals , Cell Line , Chagas Disease/etiology , Chagas Disease/immunology , Chemokine CCL2/biosynthesis , Chemokine CXCL1 , Chemokines/biosynthesis , Chemotactic Factors/biosynthesis , HeLa Cells , Humans , Inflammation Mediators/metabolism , Intercellular Signaling Peptides and Proteins/biosynthesis , Interleukin-8/genetics , Mucous Membrane/immunology , Mucous Membrane/parasitology , RNA, Messenger/genetics , RNA, Messenger/metabolism , Trypanosoma cruzi/growth & development , Trypanosoma cruzi/physiology
11.
Am J Physiol Cell Physiol ; 281(6): C1837-49, 2001 Dec.
Article in English | MEDLINE | ID: mdl-11698242

ABSTRACT

Butyrate and other short-chain fatty acids (SCFAs) are found at high concentrations in the colonic lumen and affect multiple epithelial cell functions. To better understand how SCFAs regulate ion transport, we investigated the effects of SCFAs on Cl(-) secretion in human colonic epithelial cell line T(84). Butyrate inhibited Cl(-) secretory responses to prostaglandin E(2), forskolin, and cholera toxin. Other SCFAs were less effective or inactive. Reduced secretion was associated with decreased synthesis of the second messenger cAMP rather than increased degradation. Expression and activity of adenylyl cyclase were decreased by butyrate, whereas phosphodiesterase activity was unaffected and phosphodiesterase inhibition did not reverse the effects of butyrate on Cl(-) secretion. Furthermore, butyrate decreased expression of the basolateral Na-K-2Cl cotransporter, indicating that it might modulate the secretory capacity of the cells. However, butyrate did not affect secretory responses to the calcium-dependent secretagogue carbachol, cAMP analogs, or uroguanylin, indicating that normal secretory responses to adequate levels of second messengers in butyrate-treated T(84) cells are possible. These results show that butyrate affects several aspects of epithelial Cl(-) secretion, including second messenger generation and expression of key ion transporters. However, these effects may not all be equally important in determining Cl(-) secretion in response to physiologically relevant secretagogues.


Subject(s)
Adenylyl Cyclases/metabolism , Butyrates/pharmacology , Chlorides/metabolism , Intestinal Mucosa/metabolism , 1-Methyl-3-isobutylxanthine/pharmacology , Acetates/pharmacology , Butyrates/chemistry , Calcium/metabolism , Cell Line , Cholera Toxin/pharmacology , Colforsin/pharmacology , Cyclic AMP/analogs & derivatives , Cyclic AMP/metabolism , Dinoprostone/metabolism , Humans , Intestinal Mucosa/cytology , Phosphodiesterase Inhibitors/pharmacology , Propionates/pharmacology , Sodium-Potassium-Chloride Symporters/metabolism , Solute Carrier Family 12, Member 2 , Time Factors
12.
Am J Physiol Gastrointest Liver Physiol ; 280(6): G1217-26, 2001 Jun.
Article in English | MEDLINE | ID: mdl-11352815

ABSTRACT

The intestinal mucosa contains a subset of lymphocytes that produce Th2 cytokines, yet the signals responsible for the recruitment of these cells are poorly understood. Macrophage-derived chemokine (MDC/CCL22) is a recently described CC chemokine known to chemoattract the Th2 cytokine producing cells that express the receptor CCR4. The studies herein demonstrate the constitutive production of MDC/CCL22 in vivo by human colon epithelium and by epithelium of human intestinal xenografts. MDC/CCL22 mRNA expression and protein secretion was upregulated in colon epithelial cell lines in response to proinflammatory cytokines or infection with enteroinvasive bacteria. Inhibition of nuclear factor (NF)-kappaB activation abolished MDC/CCL22 expression in response to proinflammatory stimuli, demonstrating that MDC/CCL22 is a NF-kappaB target gene. In addition, tumor necrosis factor-alpha-induced MDC/CCL22 secretion was differentially modulated by Th1 and Th2 cytokines. Supernatants from the basal, but not apical, side of polarized epithelial cells induced a MDC/CCL22-dependent chemotaxis of CCR4-positive T cells. These studies demonstrate the constitutive and regulated production by intestinal epithelial cells of a chemokine known to function in the trafficking of T cells that produce anti-inflammatory cytokines.


Subject(s)
Chemokines, CC/biosynthesis , Intestinal Mucosa/metabolism , Animals , Cell Polarity/physiology , Chemokine CCL22 , Chemokines, CC/genetics , Chemokines, CC/metabolism , Chemokines, CC/pharmacology , Chemotaxis, Leukocyte/drug effects , Colon/metabolism , Cytokines/metabolism , Cytokines/pharmacology , Escherichia coli Infections/metabolism , Fetal Tissue Transplantation , Humans , Intestinal Mucosa/cytology , Intestinal Mucosa/microbiology , Intestines/embryology , Intestines/transplantation , Mice , Mice, SCID , NF-kappa B/physiology , RNA, Messenger/metabolism , Salmonella Infections/metabolism , T-Lymphocytes/physiology , Th2 Cells/metabolism , Transplantation, Heterologous , Tumor Cells, Cultured
13.
Curr Opin Microbiol ; 4(3): 246-50, 2001 Jun.
Article in English | MEDLINE | ID: mdl-11378474

ABSTRACT

Gene expression profiling offers new opportunities for understanding host-cell responses to microbial pathogens and their products. Current strategies involve either first identifying mRNAs that differ in their expression status under different experimental conditions and later defining the identity of the respective genes (for example, differential display or serial analysis of gene expression), or alternatively assessing changes in the expression of already defined genes (for example, cDNA or oligonucleotide microarrays). Early studies indicate the power of gene expression profiling for providing new insights into groups of genes whose expression is altered during the course of host-microbe interactions, and for the discovery of cellular genes that were not previously recognized to be regulated by infection.


Subject(s)
Gene Expression Profiling , Immune System/immunology , Infections/genetics , Gene Expression Profiling/methods , Gene Expression Regulation , Humans , Immune System/metabolism , Infections/immunology , Oligonucleotide Array Sequence Analysis
14.
Am J Respir Cell Mol Biol ; 24(4): 382-9, 2001 Apr.
Article in English | MEDLINE | ID: mdl-11306430

ABSTRACT

The chemokine TARC is a ligand for the chemokine receptor CCR4 expressed on T helper (Th)2-type CD4 T cells. Allergic airway inflammation is characterized by a local increase in cells secreting Th2-type cytokines. We hypothesized that bronchial epithelial cells may be a source of chemokines known to chemoattract Th2 cells. Regulated TARC expression was studied using normal human bronchial epithelial cells and a human lung xenograft model. TARC expression was increased in normal human bronchial epithelial cells in response to tumor necrosis factor-alpha stimulation, and further upregulation of TARC was observed with interferon (IFN)-gamma but not interleukin (IL)-4 costimulation. TARC functions as a nuclear factor (NF)-kappa B target gene, as shown by the abrogation of TARC expression in response to proinflammatory stimuli when NF-kappa B activation is inhibited. In an in vivo model, minimal constitutive TARC expression was observed in human lung xenografts. Consistent with our findings in vitro, TARC messenger RNA (mRNA) expression was upregulated in the xenografts in response to IL-1, and costimulation with IFN-gamma but not IL-4 further increased TARC mRNA and protein expression. In addition, bronchoalveolar lavage fluid from asthmatic subjects after allergen challenge contained significantly increased levels of TARC, suggesting that TARC production by bronchial epithelial cells may play a role in the pathogenesis of allergic asthma.


Subject(s)
Bronchi/cytology , Chemokines, CC/genetics , Epithelial Cells/immunology , Lung Transplantation/immunology , Th2 Cells/immunology , Animals , Bronchoalveolar Lavage Fluid/chemistry , Bronchoalveolar Lavage Fluid/immunology , Cell Line, Transformed , Chemokine CCL17 , Chemokines, CC/analysis , Epithelial Cells/cytology , Fetal Tissue Transplantation , Gene Expression Regulation, Neoplastic , Humans , In Vitro Techniques , Lung Neoplasms , Mice , Mice, Inbred C57BL , Mice, SCID , NF-kappa B/genetics , RNA, Messenger/analysis , Transplantation, Heterologous , Tumor Cells, Cultured
15.
Am J Physiol Gastrointest Liver Physiol ; 280(4): G710-9, 2001 Apr.
Article in English | MEDLINE | ID: mdl-11254498

ABSTRACT

Human intestinal epithelial cells secrete an array of chemokines known to signal the trafficking of neutrophils and monocytes important in innate mucosal immunity. We hypothesized that intestinal epithelium may also have the capacity to play a role in signaling host adaptive immunity. The CC chemokine macrophage inflammatory protein (MIP)-3alpha/CCL20 is chemotactic for immature dendritic cells and CD45RO(+) T cells that are important components of the host adaptive immune system. In these studies, we demonstrate the widespread production and regulated expression of MIP-3alpha by human intestinal epithelium. Several intestinal epithelial cell lines were shown to constitutively express MIP-3alpha mRNA. Moreover, MIP-3alpha mRNA expression and protein production were upregulated by stimulation of intestinal epithelial cells with the proinflammatory cytokines tumor necrosis factor-alpha or interleukin-1alpha or in response to infection with the enteric bacterial pathogens Salmonella or enteroinvasive Escherichia coli. In addition, MIP-3alpha was shown to function as a nuclear factor-kappaB target gene. In vitro findings were paralleled in vivo by increased expression of MIP-3alpha in the epithelium of cytokine-stimulated or bacteria-infected human intestinal xenografts and in the epithelium of inflamed human colon. Mucosal T cells, other mucosal mononuclear cells, and intestinal epithelial cells expressed CCR6, the cognate receptor for MIP-3alpha. The constitutive and regulated expression of MIP-3alpha by human intestinal epithelium is consistent with a role for epithelial cell-produced MIP-3alpha in modulating mucosal adaptive immune responses.


Subject(s)
Chemokines, CC , Immunity, Mucosal/immunology , Intestinal Mucosa/immunology , Intestinal Mucosa/metabolism , Macrophage Inflammatory Proteins/biosynthesis , Adenoviridae/immunology , Animals , Chemokine CCL20 , Enzyme-Linked Immunosorbent Assay , Epithelium/immunology , Epithelium/metabolism , Fetal Tissue Transplantation , Humans , Indicators and Reagents , Interleukin-1/pharmacology , Macrophage Inflammatory Proteins/immunology , Mice , Mice, Inbred C57BL , Receptors, CCR6 , Receptors, Chemokine/biosynthesis , Receptors, Chemokine/genetics , Repressor Proteins/physiology , Salmonella Infections/metabolism , Transplantation, Heterologous , Tumor Cells, Cultured , Up-Regulation/genetics
16.
Gastroenterology ; 120(1): 49-59, 2001 Jan.
Article in English | MEDLINE | ID: mdl-11208713

ABSTRACT

BACKGROUND & AIMS: Human intestinal epithelial cells inducibly express neutrophil and monocyte chemoattractants, yet little is known about the regulated production of T-cell chemoattractants by the intestinal epithelium. IP-10, Mig, and I-TAC are 3 CXC chemokines that are known to act as CD4(+) T-cell chemoattractants. METHODS: We studied constitutive chemokine expression in human colon, and defined the regulated expression of these chemokines by reverse-transcription polymerase chain reaction, enzyme-linked immunosorbent assay, and immunohistology using cultured human intestinal epithelial cell lines and a novel adaptation of an in vivo human intestinal xenograft model. RESULTS: IP-10 and Mig were constitutively expressed by normal human colon epithelium, and their cognate receptor, CXCR3, was expressed by mucosal mononuclear cells. Interferon (IFN)-gamma stimulation increased mRNA expression and the polarized basolateral secretion of these chemokines by human colon epithelial cell lines; infection with enteroinvasive bacteria, or stimulation with the proinflammatory cytokines tumor necrosis factor alpha and interleukin 1alpha, strongly potentiated IFN-gamma-induced epithelial cell IP-10, Mig, and I-TAC production. Epithelial cell mRNA and protein expression of IP-10, Mig, and I-TAC were rapidly up-regulated in human intestinal xenografts in response to stimulation with IFN-gamma alone or in combination with IL-1. CONCLUSIONS: The constitutive and regulated production of the IFN-gamma-inducible chemokines IP-10, Mig, and I-TAC by human intestinal epithelium, and the expression of their cognate receptor, CXCR3, by mucosal mononuclear cells, suggest that the intestinal epithelium can play a role in modulating physiologic and pathologic T cell-mediated mucosal inflammation.


Subject(s)
Antineoplastic Agents/pharmacology , CD4-Positive T-Lymphocytes/cytology , Chemokines, CXC/metabolism , Chemotaxis, Leukocyte/physiology , Intercellular Signaling Peptides and Proteins , Interferon-gamma/pharmacology , Intestinal Mucosa/immunology , Animals , Bacterial Infections/immunology , Bacterial Infections/metabolism , CD4-Positive T-Lymphocytes/immunology , Chemokine CXCL10 , Chemokine CXCL11 , Chemokine CXCL9 , Chemokines, CXC/genetics , Chemotaxis, Leukocyte/drug effects , Enteritis/immunology , Enteritis/metabolism , Fetal Tissue Transplantation , Fetus/cytology , Gene Expression/physiology , HT29 Cells , Humans , Interleukin-13/metabolism , Interleukin-4/metabolism , Intestinal Mucosa/cytology , Intestinal Mucosa/metabolism , Mice , Mice, Inbred C57BL , Mice, SCID , Neoplasm Transplantation , RNA, Messenger/analysis , Receptors, CXCR3 , Receptors, Chemokine/genetics , Receptors, Chemokine/metabolism , Transplantation, Heterologous
17.
Article in English | MEDLINE | ID: mdl-11123191

ABSTRACT

Giardia lamblia is one of the most important causes of waterborne diarrheal disease worldwide, and giardiasis is the most common protozoan infection of the human small intestine. Symptomatic infection is characterized by diarrhea, abdominal pain, and malabsorption, leading to malnutrition and weight loss, particularly in children. The pathogen resides strictly in the lumen of the small intestine, and infection is typically not accompanied by significant mucosal inflammation. Clinical and experimental studies indicate that B cell-dependent host defenses, particularly IgA, are important for controlling and clearing Giardia infection, although B cell-independent mechanisms also contribute to this outcome. In contrast to antigiardial host defenses, much less is known about the pathophysiological mechanisms underlying the clinical symptoms of giardiasis, partly because of the current lack of suitable model systems. In addition to being an important human enteric pathogen, Giardia is an interesting model organism for gaining basic insights into genetic innovations that led to evolution of eukaryotic cells, since it belongs to the earliest diverging eukaryotic lineage known. The completion of the giardial genome project will increase understanding of the basic biology of the protozoan and will help us to better understand host pathogen-interactions as a basis for developing new vaccination and therapeutic strategies.


Subject(s)
Giardia lamblia/metabolism , Giardiasis/metabolism , Host-Parasite Interactions/immunology , Intestinal Mucosa/parasitology , Toxins, Biological/metabolism , Animals , Diarrhea/immunology , Diarrhea/metabolism , Diarrhea/parasitology , Giardiasis/immunology , Humans , Intestinal Mucosa/immunology , Intestinal Mucosa/metabolism
18.
Microbes Infect ; 3(14-15): 1191-200, 2001.
Article in English | MEDLINE | ID: mdl-11755407

ABSTRACT

Cytokines are key communication molecules between host cells in the defense against the enteric pathogen, Salmonella. Infection with Salmonella induces expression of multiple chemokines and proinflammatory cytokines in cultured intestinal epithelial cells and macrophages. In animal models, protective roles have been shown for IL-1alpha, TNFalpha, IFN-gamma, IL-12, IL-18 and IL-15, whereas IL-4 and IL-10 inhibit host defenses against Salmonella.


Subject(s)
Cytokines/biosynthesis , Immunity, Innate , Salmonella Infections/immunology , Salmonella/pathogenicity , Animals , Cells, Cultured , Disease Models, Animal , Epithelium/microbiology , Humans , Intestines/cytology , Intestines/microbiology , Macrophages/microbiology , Mice , Salmonella/physiology , Salmonella Infections/microbiology
19.
J Biol Chem ; 275(19): 14084-94, 2000 May 12.
Article in English | MEDLINE | ID: mdl-10799483

ABSTRACT

Many clinically important enteric pathogens initiate disease by invading and passing through the intestinal epithelium, a process accompanied by increased epithelial expression of proinflammatory cytokines. To further define the role intestinal epithelial cells play in initiating and modulating the host response to infection with invasive bacteria, hybrid selection on high density cDNA arrays was used to characterize the mRNA expression profile of approximately 4,300 genes in human intestinal epithelial cells after infection with the prototypic invasive bacteria, Salmonella. Selected findings were further evaluated by reverse transcription-polymerase chain reaction, Northern blot analysis, and protein assays. Epithelial infection with Salmonella significantly up-regulated mRNA expression of a relatively small fraction of all genes tested. Of these, several cytokines (granulocyte colony-stimulating factor, inhibin A, Epstein-Barr virus-induced gene 3, interleukin-8, macrophage inflammatory protein-2alpha), kinases (TKT, Eck, HEK), transcription factors (interferon regulatory factor-1), and HLA class I were the most prominent. Furthermore, the transcription factor NF-kappaB is shown to be important for inducible mRNA expression for a broad group of genes tested. These findings expand the repertoire of known epithelial cell responses to infection with an invasive enteric pathogen. The results also show that evaluation of mRNA expression profiles by cDNA array analysis is a powerful approach to characterizing and understanding host-pathogen interactions.


Subject(s)
Gene Expression Regulation, Bacterial , Intestinal Mucosa/metabolism , Intestinal Mucosa/microbiology , Salmonella/pathogenicity , Base Sequence , Blotting, Northern , Cytokines/genetics , DNA Primers , DNA, Complementary , Gene Expression Regulation, Bacterial/physiology , HT29 Cells , Humans , NF-kappa B/physiology , RNA, Messenger/genetics , Reverse Transcriptase Polymerase Chain Reaction
20.
Infect Immun ; 68(3): 1710-3, 2000 Mar.
Article in English | MEDLINE | ID: mdl-10678994

ABSTRACT

Cryptosporidium parvum induces moderate levels of apoptosis of cultured human intestinal epithelial cells, which are maximal at 24 h after infection. Apoptosis is further increased in C. parvum-infected cells by inhibition of NF-kappaB. C. parvum infection also attenuates epithelial apoptosis induced by strongly proapoptotic agents. The data suggest C. parvum has developed strategies to limit apoptosis in order to facilitate its growth and maturation in the early period after epithelial cell infection.


Subject(s)
Apoptosis , Cryptosporidium parvum/physiology , Intestinal Mucosa/parasitology , Animals , Humans , Intestinal Mucosa/pathology , NF-kappa B/physiology , Tumor Cells, Cultured
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