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PubMed2004

Curcumin blocks NF-kappaB and the motogenic response in Helicobacter pylori-infected epithelial cells.

Infection of epithelial cells by the microbial pathogen Helicobacter pylori leads to activation of the transcription factor nuclear factor kappaB (NF-kappaB), the induction of pro-inflammatory cytokine/chemokine genes, and the motogenic response (cell scattering). Here we report that H. pylori-induced NF-kappaB activation and the subsequent release of interleukin 8 (IL-8) are inhibited by curcumin (diferuloylmethane), a yellow pigment in turmeric (Curcuma longa L.). Our results demonstrate that curcumin inhibits IkappaBalpha degradation, the activity of IkappaB kinases alpha and beta (IKKalpha and beta), and NF-kappaB DNA-binding. The mitogen-activated protein kinases (MAPK), extracellular signal-regulated kinases 1/2 (ERK1/2) and p38, which are also activated by H. pylori infection, were not inhibited by curcumin. Further, the H. pylori-induced motogenic response was blocked by curcumin. We conclude that curcumin, due to inhibition of NF-kappaB activation and cell scattering, should be considered as a potential therapeutic agent effective against pathogenic processes initiated by H. pylori infection.

Anti-Inflammatory Agents, Non-Steroidal↗

PubMed2000

Localization of dysfunctional tight junctions in Salmonella enterica serovar typhimurium-infected epithelial layers.

Infection of polarized MDCK epithelial layers by Salmonella enterica serovar Typhimurium is accompanied by increased tight junction permeability and by contraction of perijunctional actinomyosin. We localized dysfunctional tight junctions in serovar Typhimurium-infected MDCK layers by imaging apical-basolateral intramembrane diffusion of fluorescent lipid and found that loss of the apical-basolateral diffusion barrier (tight junction fence function) was most marked in areas of prominent perijunctional contraction. The protein kinase inhibitor staurosporine prevented perijunctional contraction but did not reverse the effects of serovar Typhimurium on tight junction barrier function. Hence, perijunctional contraction is not required for Salmonella-induced tight junction dysfunction and this epithelial response to infection may be multifactorial.

Animals↗

PubMed1999

Epstein-Barr virus (EBV) infection and gastric carcinoma: the approach through EBV infected epithelial cell lines.

Epstein-Barr virus (EBV) infection is found in 7% of Japanese gastric carcinoma. Our strategy is to establish the EBV infected epithelial cell lines from EBV infected gastric carcinomas and to characterize the cell lines on the bases of cellular and molecular biology to define the etiological role of EBV. We have characterized two EBV positive cell lines, GT38 and GT39 from gastric tissues. The both cell lines were EBV latency type III and produced the virus spontaneously. The character of tumor cells was demonstrated by the colony formation in soft agar and the tumorigenesis in severe combined immunodeficient mice.

Animals↗

PubMed1998

Influenza virus-infected epithelial cells present viral antigens to antigen-specific CD8+ cytotoxic T lymphocytes.

We have investigated the mechanisms involved in the clearance of viral infection at the epithelium level by analyzing the activity of influenza virus-specific cytotoxic T lymphocytes (CTL) against virus-infected CMT-93 intestinal epithelial cells. Epithelial cells infected with live influenza virus effectively present viral antigens and were lysed by both homotypic and heterotypic influenza virus-specific CD8+ T cells. These results shed new light on the control of viral infection through the elimination of virus-infected epithelial cells by virus-specific CTL and demonstrate that CMT-93 cells furnish an appropriate model for in vitro evaluation of CTL activity against virus-infected epithelial cells.

Animals↗

PubMed2003

Cervical human papillomavirus infection; epithelial abnormalities in human immunodeficiency virus infected women.

OBJECTIVE: The aim of the study was to determine the prevalence of cervical infection with human papillomavirus (HPV) in human immunodeficiency virus (HIV) infected women. MATERIALS AND METHODS: Cervical Papanicolaou tests, colposcopy and biopsies were performed in 21 HIV seropositive women. RESULTS: Four patients (19%) had an abnormal smear test, one had CIN-II (4.7%) and three had cervical warts (14.2%).

Colposcopy↗

PubMed2001

Effect of transforming growth factor-beta1 on the cell growth and Epstein-Barr virus reactivation in EBV-infected epithelial cell lines.

Transforming growth factor (TGF)-beta1 is a multifunctional cytokine that plays important roles in regulating cell growth and differentiation in many biological systems. In this study, we found that gastric tissue-derived Epstein-Barr virus (EBV)-infected epithelial cell lines GT38 and GT39 had resistance to TGF-beta1-mediated growth inhibition and apoptosis compared to a TGF-beta1-susceptible gastric carcinoma cell line HSC-39. However, TGF-beta1 partially induced EBV reactivation in GT38 and GT39 cells, as shown by the induction of EBV immediate-early BZLF1 RNA and its protein product ZEBRA and early antigen-D. The expressions of TGF-beta receptor I and II were detected in GT38 and GT39 cells by Northern and Western blot analyses. Both cell lines spontaneously produced the TGF-beta1, which was sufficient for inhibiting cell growth of HSC-39 cells. Taken together, these data suggest that TGF-beta1 may be a key factor for EBV reactivation and selective growth of EBV-infected epithelial cells in vivo.

Activin Receptors, Type I↗

PubMed1994

Antigen expressed by Salmonella typhimurium is processed for class I major histocompatibility complex presentation by macrophages but not infected epithelial cells.

Macrophages were shown to mediate class I major histocompatibility complex (MHC-1) presentation of a fusion protein (Crl-OVA) expressed in Salmonella typhimurium, a bacterium which fails to escape from vacuolar compartments after phagocytosis or penetration into host cells. Salmonella typhimurium also penetrates into non-phagocytic intestinal epithelial cells, a portal of entry for systemic infection. We tested the ability of infected epithelial cells to process antigen expressed by S. typhimurium for presentation by MHC-I molecules to CD8+ T cells. CMT-93 murine adenocarcinoma cells expressed Kb and effectively presented the OVA 257-264 peptide to CD8 OVA T-hybridoma cells, but infected CMT-93 cells failed to process Crl-OVA expressed in S. typhimurium. Therapeutically useful MHC-I-restricted cytotoxic T-lymphocyte (CTL) responses may be generated by macrophage presentation of Salmonella antigens or recombinant antigens expressed in Salmonella vaccine vectors. Our data suggest that an inability of epithelial cells to present these antigens may limit the utility of CTL in epithelial immunity in salmonellosis, but studies of additional epithelial cell systems are needed.

Animals↗

PubMed2004

SF2/ASF binds the human papillomavirus type 16 late RNA control element and is regulated during differentiation of virus-infected epithelial cells.

Pre-mRNA splicing occurs in the spliceosome, which is composed of small ribonucleoprotein particles (snRNPs) and many non-snRNP components. SR proteins, so called because of their C-terminal arginine- and serine-rich domains (RS domains), are essential members of this class. Recruitment of snRNPs to 5' and 3' splice sites is mediated and promoted by SR proteins. SR proteins also bridge splicing factors across exons to help to define these units and have a central role in alternative and enhancer-dependent splicing. Here, we show that the SR protein SF2/ASF is part of a complex that forms upon the 79-nucleotide negative regulatory element (NRE) that is thought to be pivotal in posttranscriptional regulation of late gene expression in human papillomavirus type 16 (HPV-16). However, the NRE does not contain any active splice sites, is located in the viral late 3' untranslated region, and regulates RNA-processing events other than splicing. The level of expression and extent of phosphorylation of SF2/ASF are upregulated with epithelial differentiation, as is subcellular distribution, specifically in HPV-16-infected epithelial cells, and expression levels are controlled, at least in part, by the virus transcription regulator E2.

3' Untranslated Regions↗

PubMed2005

The pilus and porin of Neisseria gonorrhoeae cooperatively induce Ca(2+) transients in infected epithelial cells.

Purified pili and porin from Neisseria quickly mobilize calcium (Ca(2+)) stores in monocytes and epithelial cells, ultimately influencing host cell viability as well as bacterial intracellular survival. Here, we examined the Ca(2+) transients induced in human epithelial cells during infection by live, piliated N. gonorrhoeae. Porin induced an influx of Ca(2+) from the extracellular medium less than 60 s post infection. The porin-induced transient is followed by a pilus-induced release of Ca(2+) from intracellular stores. The timing of these events is similar to that observed using purified proteins. Interestingly, the porin-induced Ca(2+) flux is required for the pilus-induced transient, indicating that the pilus-induced Ca(2+) release is, itself, Ca(2+) dependent. Several lines of evidence indicate that porin is present on pili. Moreover, pilus retraction strongly influences the porin- and pilus-induced Ca(2+) fluxes. These and other results strongly suggest that the pilus and porin cooperate to modulate calcium signalling in epithelial cells, and propose a model to explain how N. gonorrhoeae triggers Ca(2+) transients in the initial stages of pilus-mediated attachment.

Calcium↗

PubMed1980

Polarized distribution of viral envelope proteins in the plasma membrane of infected epithelial cells.

The surface distribution of the envelope glycoproteins of influenza, Sendai and Vesicular Stomatitis viruses was studied by immunofluorescence and immunoelectromicroscopy in infected epithelial cell monolayers, from which these viruses bud in a polarized fashion. It was found that before the onset of viral budding, the envelope proteins are exclusively localized into the same plasma membrane domains of the epithelial cells from which the virions ultimately bud: the glycoproteins of influenza and Sendai were detected at the apical surface, while the G protein of Vesicular Stomatitis virus was concentrated at the basolateral region. On the other hand, Sendai virus nucleocapsids, which can be easily identified in the cytoplasm before viral assembly, could be observed throughout the cell, not showing any preferential localization near the surface that the virions utilize for budding. These results are consistent with a model in which the asymmetric distribution of viral envelope proteins, rather than a polarized delivery of nucleocapsids, directs the polarity of viral budding. Furthermore, the asymmetric surface localization of viral glycoproteins suggests that these proteins share with intrinsic surface proteins of epithelial cells common biogenetic mechanisms and informational features or "sorting out" signals that determine their compartmentalization in the plasma membrane.

Animals↗

PubMed2001

Spontaneous reduction in Epstein-Barr virus (EBV) DNA copy number in EBV-infected epithelial cell lines.

We found that spontaneous and 12-0-tetradecanoylphorbol-13-acetate-induced Epstein-Barr virus (EBV) reactivation occurred in short-term (ST)-cultured EBV-infected epithelial cell lines GT38 and GT39 after their establishment; however, it diminished in the long-term (LT)-cultured cells passaged for more than 2 years from ST-cultured cells. We hypothesized that the EBV reactivation may be related to the EBV DNA copy number in the cells. A higher level of EBV DNA content was detected in ST-cultured cells than in LT-cultured cells by Southern hybridization using an EBV DNA XhoI probe. Fluorescence in situ hybridization using EBV DNA BamHI W fragments showed that ST-cultured cells contained a higher EBV DNA copy number than that of LT-cultured cells. EBV DNA-negative cells were detected in small proportions in LT-cultured cells, but were undetected in ST-cultured cells. These results demonstrate that EBV genomes are not maintained stably in the cell lines, and some of them are lost in continuous passages of the cells. We discuss the mechanisms of reduction of EBV reactivation and EBV DNA in the cell lines.

Animals↗

PubMed1989

Stable expression of lipooligosaccharide antigens during attachment, internalization, and intracellular processing of Neisseria gonorrhoeae in infected epithelial cells.

Immunoelectron microscopy enables the detection and localization of bacterial antigens during in vitro infection (J.F.L. Weel and J.P.M. van Putten, Microb. Pathog. 4:213-222, 1988). In this study, we have used this method to get information on the role of lipooligosaccharides (LOS) in the pathogenesis of neisserial infections at the mucosal level. Ultrathin cryosections of Chang conjunctive epithelial cells infected with Neisseria gonorrhoeae (3 to 18 h) were incubated with LOS-specific monoclonal antibodies and gold-labeled protein A and viewed in the electron microscope. Our results demonstrate that the probed LOS determinants are stably expressed during the adherence, internalization, and intracellular processing of the bacteria. There was no indication of an adaptation of the gonococcal LOS expression to the host cell environment or of a degradation of the probed epitopes. The gold particles, representing LOS molecules, were predominantly located at the bacterial membranes, but sometimes the host cell plasma membrane was labeled as well, suggesting that LOS or LOS-containing membrane fragments interacted with the eucaryotic cells. This was confirmed when purified LOS was added to the cells. Two hours after LOS exposure, gold particles were observed at the plasma membrane of a subpopulation of the cells. After 18 h of LOS exposure, gold particles were also found in large vacuoles inside the cells, suggesting that LOS molecules were internalized by the cells. The function of observed LOS binding and endocytosis in the pathogenesis of neisserial infections remains to be defined.

Antibodies, Bacterial↗

PubMed1998

Role of fimbriae-mediated adherence for neutrophil migration across Escherichia coli-infected epithelial cell layers.

This study examined the role of P and type 1 fimbriae for neutrophil migration across Escherichia coli-infected uroepithelial cell layers in vitro and for neutrophil recruitment to the urinary tract in vivo. Recombinant E. coli K-12 strains differing in P or type 1 fimbrial expression were used to infect confluent epithelial layers on the underside of transwell inserts. Neutrophils were added to the upper well, and their passage across the epithelial cell layers was quantified. Infection with the P- and type 1-fimbriated recombinant E. coli strains stimulated neutrophil migration to the same extent as a fully virulent clinical E. coli isolate, but the isogenic non-fimbriated vector control strains had no stimulatory effect. The enhancement of neutrophil migration was adhesion dependent; it was inhibited by soluble receptor analogues blocking the binding of P fimbriae to the globoseries of glycosphingolipids or of type 1 fimbriae to mannosylated glycoprotein receptors. P- and type 1-fimbriated E. coli triggered higher interleukin (IL) 8 secretion and expression of functional IL-8 receptors than non-fimbriated controls, and the increase in neutrophil migration across infected cell layers was inhibited by anti-IL-8 antibodies. In a mouse infection model, P- or type 1-fimbriated E. coli stimulated higher chemokine (MIP-2) and neutrophil responses than the non-fimbriated vector controls. The results demonstrated that transformation with the pap or fim DNA sequences is sufficient to convert an E. coli K-12 strain to a host response inducer, and that fimbriation enhances neutrophil recruitment in vitro and in vivo. Epithelial chemokine production provides a molecular link between the fimbriated bacteria that adhere to epithelial cells and tissue inflammation.

Animals↗

PubMed1991

In situ expression and localization of Neisseria gonorrhoeae opacity proteins in infected epithelial cells: apparent role of Opa proteins in cellular invasion.

During natural infection, gonococcal opacity proteins (Opa) undergo rapid phase variation, but how this phenomenon contributes to the virulence of the bacteria is not well understood. In the present immunomorphological study we examined the actual Opa status of individual gonococci during various stages of gonococcal infection of Chang epithelial cells, by probing ultrathin sections of infected specimens with Opa-specific monoclonal antibodies. Our results demonstrate a heterogeneous Opa expression during the initial interaction of the bacteria, but an almost 100% expression of one of the probed Opas during their secondary attachment and entry into the host cells, suggesting a role for distinct Opas in cellular penetration. The association between Opa expression, tight attachment, and bacterial invasion into the host cells could be confirmed with isogenic variants that expressed different Opa proteins. Once inside the epithelial cells, both morphologically intact, Opa positive and morphologically disintegrated, Opa negative bacteria were observed. The loss of Opa immunoreactivity in intracellular gonococci could not be related to the presence of a particular Opa protein, but could be mimicked by incubating the organisms with extracts of sonicated uninfected epithelial cells, suggesting that it was caused by host cell proteolytic activity. Taken together, our data suggest that Opa phase transitions confer a functional adaptation of the bacteria enabling host cell penetration.

Antigens, Bacterial↗

PubMed2006

Antibodies to gp350/220 enhance the ability of Epstein-Barr virus to infect epithelial cells.

Epstein-Barr virus (EBV) is a persistent, orally transmitted herpesvirus that replicates in B cells and epithelial cells and is associated with lymphoid and epithelial malignancies. The virus binds to CD21 on B cells via glycoprotein gp350/220 and infects efficiently. Infection of cultured epithelial cells has not typically been efficient but can occur in the absence of gp350/220 and CD21 and in vivo is thought to be important to the development of nasopharyngeal carcinoma. We report here that antibodies to gp350/220, which inhibit EBV infection of B cells, enhance infection of epithelial cells. The effect is not mediated by Fc receptor binding but is further enhanced by antibody cross-linking, which may patch gp350/220 in the virus envelope. Saliva from EBV-seropositive individuals has similar effects that can be reversed by depletion of antibody. The results are consistent with a model in which gp350/220 interferes with the access of other important players to the epithelial cell surface. The results may have implications for the development of nasopharyngeal carcinoma in high-risk populations in which elevated titers of antibody to EBV lytic cycle proteins are prognostic.

Antibodies↗

PubMed2005

Lipooligosaccharide-independent alteration of cellular homeostasis in Neisseria meningitidis-infected epithelial cells.

Neisseria meningitidis (MC) is an important cause of meningitis and septic shock. Primary loose attachment of MC to host epithelial cells is mediated by type IV pili. Lipooligosaccharide (LOS), opacity (Opa) proteins and glycolipid adhesins facilitate subsequent tight attachment. MC infection causes numerous changes in host epithelial cell homeostasis. These include cortical plaque formation, increased expression of proinflammatory cytokines and alterations in host iron homeostasis. Using both biochemical and genetic approaches, we examined the role of LOS in mediating these events. We first examined specific cellular iron homeostasis changes that occur following addition of purified MC LOS to epithelial cells. Using an MC mutant that completely lacks LOS (MC lps tbp), we examined pili-mediated attachment and cortical plaque formation in human endocervical epithelial cells (A431). We also tested whether the lack of LOS alters cellular homeostasis, including changes in the levels of host stress response factors and proinflammatory cytokines. MC lps tbp elicited the formation of cortical plaques in A431 cells. However, the plaques were less pronounced than those formed by the MC parent. Surprisingly, the proinflammatory cytokine TNF(alpha) was upregulated during infection in MC lps tbp-infected cells. Furthermore, alterations in iron homeostasis, including lower transferrin receptor 1 (TfR-1) levels, altered TfR-1 trafficking, an 'iron-starvation' gene expression profile and low iron regulatory protein (IRP) binding activity are independent of LOS. Our results demonstrate that LOS is partially involved in both the attachment to host cells and formation of cortical plaques. However, TNFalpha induction and changes in iron homeostasis observed in MC-infected epithelial cells are independent of LOS.

Bacterial Adhesion↗

PubMed2001

Cytochrome c-mediated caspase-9 activation triggers apoptosis in Streptococcus pyogenes-infected epithelial cells.

Epithelial cells are the initial sites of host invasion by group A Streptococcus pyogenes (GAS), and their infection of epithelial cells has been suggested to induce apoptosis. However, the mechanism responsible for bacteria-host interaction and the induction of apoptosis has not been clearly understood. We demonstrate here that human pharyngeal epithelial HEp-2 cells became apoptotic with DNA fragmentation by invasion of GAS strains JRS4 (M6+, F1+) and JRS145 (M6-, F1+ mutant of JRS4), whereas apoptotic cellular changes were not observed in SAM1 (M6+, F1- mutant) or SAM2 (M6-, F1- mutant) infected HEp-2 cells. Confocal microscopy revealed that Bax translocation to mitochondria and cytochrome c release occurred after 4 h of infection. Western blot analyses showed that the amounts of Bcl-2 and Bcl-xL were decreased in the mitochondria of infected cells. In addition, we demonstrated that the release of nuclear histone from infected cells was prevented by the addition of caspase-9 inhibitor (Ac-LEHD-CHO). We conclude that the internalization of GAS in epithelial cells is necessary and sufficient for the induction of apoptosis, which is initiated by mitochondrial dysfunction, and the mechanism of GAS-induced apoptosis is clearly different from that induced by other intracellular invasive bacteria, e.g. Shigella and Salmonella species.

Apoptosis↗

PubMed2004

Transcriptome analysis and gene expression profiles of early apoptosis-related genes in Streptococcus pyogenes-infected epithelial cells.

Epithelial cells are the initial sites of host invasion by group A Streptococcus pyogenes (GAS), and GAS infection of epithelial cells has been suggested to induce apoptosis. We previously reported that the induction of apoptosis is strongly associated with the protein F1-mediated invasion. We present here the gene expression profiles of the human epithelial HEp-2 cells during GAS-induced apoptosis, using serial gene analysis of expression (SAGE) analysis and macroarray analysis of apoptosis-related genes. Serial gene analysis of expression revealed the downregulation of voltage-dependent anion channels 1 and 2 genes and the upregulation of the cytochrome c oxidase and calcium binding protein genes (calpactin, calgizzarin and programmed cell death 6). Macroarray analysis and quantitative RT-PCR analysis also revealed that the genes for IL-1beta, IL-12 p35, IL12 p40, and GM-CSF are also markedly induced by GAS invasion. Furthermore, caspase-1, -9, and -14 genes are significantly upregulated during GAS invasion. These observations indicated that apoptosis associated with GAS invasion is mainly induced by mitochondrial dysfunction and calcium regulation as well as by stress, and that these transcriptional controls may regulate the cellular response to GAS invasion.

Apoptosis↗