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• W2034504117 abstract "Invasion of the human colonic epithelium by Shigella flexneri causes inflammation that disrupts the intestinal barrier. Invaded intestinal epithelial cells are the major source of mediators recruiting the inflammatory infiltrate. To better characterize the global response of intestinal epithelial cells to Shigella invasion, Caco-2 cells were infected by an invasive isolate of S. flexneri 5a, and their transcriptome was analyzed by Affymetrix (Santa Clara, CA) microarrays (12,000 genes) and compared with these elicited by a non-invasive Shigella mutant and tumor necrosis factor (TNF)-α. The invasive and non-invasive strains enhanced transcription of a common pattern of 240 genes, among which genes encoding isoforms of cytochrome P-450 were induced. These genes were not induced by TNF-α. Conversely, both the invasive strain and TNF-α induced a common set of 18 genes, mainly encoding proinflammatory molecules. They also induced specific sets of genes. The transcriptome induced by the invasive strain was characterized by the induction of early genes (i.e. expressed within the first 45 min of invasion) and late genes (i.e. after 60 min of invasion) whose pattern was strongly biased toward stimulation of granulopoiesis, chemoattraction, activation, and adherence of polymorphonuclear leukocytes. When compared with a non-invasive Shigella and TNF-α, invasive Shigella induced a narrow transcriptome that seems to program infected epithelial cells to recruit a mucosal polymorphonuclear leukocyte to infiltrate. Dramatic increase in IL-8 gene transcription points to this chemokine as the major molecule orchestrating mucosal inflammation in shigellosis. Invasion of the human colonic epithelium by Shigella flexneri causes inflammation that disrupts the intestinal barrier. Invaded intestinal epithelial cells are the major source of mediators recruiting the inflammatory infiltrate. To better characterize the global response of intestinal epithelial cells to Shigella invasion, Caco-2 cells were infected by an invasive isolate of S. flexneri 5a, and their transcriptome was analyzed by Affymetrix (Santa Clara, CA) microarrays (12,000 genes) and compared with these elicited by a non-invasive Shigella mutant and tumor necrosis factor (TNF)-α. The invasive and non-invasive strains enhanced transcription of a common pattern of 240 genes, among which genes encoding isoforms of cytochrome P-450 were induced. These genes were not induced by TNF-α. Conversely, both the invasive strain and TNF-α induced a common set of 18 genes, mainly encoding proinflammatory molecules. They also induced specific sets of genes. The transcriptome induced by the invasive strain was characterized by the induction of early genes (i.e. expressed within the first 45 min of invasion) and late genes (i.e. after 60 min of invasion) whose pattern was strongly biased toward stimulation of granulopoiesis, chemoattraction, activation, and adherence of polymorphonuclear leukocytes. When compared with a non-invasive Shigella and TNF-α, invasive Shigella induced a narrow transcriptome that seems to program infected epithelial cells to recruit a mucosal polymorphonuclear leukocyte to infiltrate. Dramatic increase in IL-8 gene transcription points to this chemokine as the major molecule orchestrating mucosal inflammation in shigellosis. Enteroinvasive bacteria stimulate mucosal inflammation that controls infection at the cost of severe tissue destruction. The acute recto-colitis that follows epithelial invasion by Shigella (1Mathan M.M. Mathan V.I. Rev. Infect. Dis. 1991; 13: S314-SS318Crossref PubMed Scopus (101) Google Scholar), a Gram-negative invasive pathogen for humans and primates, is a paradigm of this process (2Sansonetti P.J. FEMS Microbiol. Rev. 2001; 25: 3-14PubMed Google Scholar). PMN 1The abbreviations used are: PMN, polymorphonuclear leukocytes; IEC, intestinal epithelial cells; TNF, tumor necrosis factor; EGF, epidermal growth factor; TGF, transforming growth factor; TLR, Toll-like receptors; CYP, cytochromes P-450; VIP, vasoactive intestinal polypeptide; IFN, interferon; GM-CSF, granulocyte-macrophage colony-stimulating factor; CLARP, caspase-like apoptosis-regulating protein.1The abbreviations used are: PMN, polymorphonuclear leukocytes; IEC, intestinal epithelial cells; TNF, tumor necrosis factor; EGF, epidermal growth factor; TGF, transforming growth factor; TLR, Toll-like receptors; CYP, cytochromes P-450; VIP, vasoactive intestinal polypeptide; IFN, interferon; GM-CSF, granulocyte-macrophage colony-stimulating factor; CLARP, caspase-like apoptosis-regulating protein. are massively recruited to the infected epithelial lining through which they translocate, thereby causing rupture of the epithelial barrier that, in turn, facilitates further bacterial invasion (3Perdomo J.J. Cavaillon J.M. Huerre M. Ohayon H. Gounon P. Sansonetti P.J. J. Exp. Med. 1994; 180: 1307-1319Crossref PubMed Scopus (248) Google Scholar, 4Perdomo J.J. Gounon P. Sansonetti P.J. J. Clin. Invest. 1994; 93: 633-643Crossref PubMed Scopus (163) Google Scholar) and destruction of mucosal tissues. In parallel, PMN achieve degradation of pathogenicity molecules and bacterial killing (5Mandic-Mullec I. Weiss J. Zychlinsky A. Infect. Immun. 1997; 65: 110-115Crossref PubMed Google Scholar, 6Weinrauch Y. Drugan D. Shapiro S.D. Weiss J. Zychlinsky A. Nature. 2002; 417: 91-94Crossref PubMed Scopus (240) Google Scholar). A central theme in the study of Shigella pathogenesis is understanding the cross-talk between bacteria and intestinal epithelial cells that leads to mucosal inflammation, a topic common to the study of inflammatory bowel diseases such as ulcerative colitis and Crohn's disease. Shigella may provide invaluable information by identifying common dysfunctions in signaling pathways. Recent studies point to infected intestinal epithelial cells (IEC) as major players in the inflammatory process, both as sentinels achieving bacterial sensing and as effectors producing mediators, particularly cytokines and chemokines, which initiate and orchestrate mucosal inflammation (7Jung H.C. Eckmann L. Yang S.K. Panja A. Fierer J. Morzycka-Wroblewska E. Kagnoff M. J. Clin. Invest. 1995; 95: 55-65Crossref PubMed Google Scholar). Mechanisms of recognition of invasive pathogens by IEC are not yet fully understood. Although the signaling cascades that elicit invasion in response to bacterial invasions may also affect proinflammatory signals, current evidence indicates that recognition of pathogen-associated molecular patterns is likely to dominate (8Philpott D. Girardin S. Sansonetti P.J. Curr. Opin. Immunol. 2001; 13: 410-416Crossref PubMed Scopus (120) Google Scholar). Extracellular recognition relies on Toll-like receptors (TLR) (9Kopp E.B. Medzhitov R. Curr. Opin. Immunol. 1999; 11: 13-18Crossref PubMed Scopus (585) Google Scholar), particularly TLR5, a receptor for flagellin, (10Gerwitz A.T. Simon P.O. Schmitt C.K. Taylor L.J. Hagedorn C.H. O'Brien A.D. Neish A.S. Madara J.L. J. Clin. Invest. 2001; 107: 99-109Crossref PubMed Scopus (318) Google Scholar, 11Hayashi F. Smith K.D. Ozinsky A. Hawn T.R. Yi E.C. Goodlett D.R. Eng J.K. Akira S. Underhill D.M. Aderem A. Nature. 2001; 410: 1099-1103Crossref PubMed Scopus (2742) Google Scholar) which is constitutively expressed by IEC, and possibly TLR2 and TLR4, which recognize bacterial lipoproteins and lipopolysaccharide, respectively, although their expression or actual function in IEC is still a matter of debate, particularly in absence of expression of CD14 (12Abreu M.T. Vora P. Faure E. Thomas L.S. Arnold E.T. Arditi M. J. Immunol. 2001; 167: 1609-1616Crossref PubMed Scopus (591) Google Scholar, 13Cario E. Podolsky D.K. Infect. Immun. 2000; 68: 7010-7017Crossref PubMed Scopus (1048) Google Scholar). In the case of Shigella, which is non-flagellated, most recent evidence indicates that bacterial recognition by IEC occurs intracellularly via an “inside-in” signaling pathway involving intracellular pathogen-associated molecular pattern recognition (14Philpott D.J Yamaoka S. Israel A. Sansonetti P.J. J. Immunol. 2000; 165: 903-914Crossref PubMed Scopus (212) Google Scholar) by a cytosolic molecule, Nod1/CARD4 (15Girardin S.E. Tournebize R. Mavris M. Page A.L. Li X. Stark G.R. Bertin J. DiStefano P.S. Yaniv M. Sansonetti P.J. Philpott D.J. EMBO Rep. 2001; 2: 736-742Crossref PubMed Scopus (521) Google Scholar, 16Inohara N. Ogura Y. Chen F.F. Muto A. Nunez G. J. Biol. Chem. 2001; 276: 2551-2554Abstract Full Text Full Text PDF PubMed Scopus (447) Google Scholar). Gram-negative peptidoglycan is the agonist of Nod1 intracellularly. 2Girardin, S. E., Boneca, I. G., Carneiro, L. A., Antignac, A., Jehanno, M., Viala, J., Tedin, K., Taha, M. K., Labigne, A., Zahringer, U., Coyle, A. J., DiStefano, P. S., Bertin, J., Sansonetti, J. J., and Philpott, D. J. (2003) Science 300, 1584–1587.2Girardin, S. E., Boneca, I. G., Carneiro, L. A., Antignac, A., Jehanno, M., Viala, J., Tedin, K., Taha, M. K., Labigne, A., Zahringer, U., Coyle, A. J., DiStefano, P. S., Bertin, J., Sansonetti, J. J., and Philpott, D. J. (2003) Science 300, 1584–1587. Both TLR and Nod lead to activation of the proinflammatory transcriptional factor, NF-κB (14Philpott D.J Yamaoka S. Israel A. Sansonetti P.J. J. Immunol. 2000; 165: 903-914Crossref PubMed Scopus (212) Google Scholar, 15Girardin S.E. Tournebize R. Mavris M. Page A.L. Li X. Stark G.R. Bertin J. DiStefano P.S. Yaniv M. Sansonetti P.J. Philpott D.J. EMBO Rep. 2001; 2: 736-742Crossref PubMed Scopus (521) Google Scholar, 17Elewaut D. DiDonato J.A. Kim J.M. Truong F. Eckmann L. Kagnoff M.F. J. Immunol. 1999; 163: 1457-1466PubMed Google Scholar, 18Neish A.S. Gewiirtz A.T. Zeng H. Young A.N. Hobert M.E. Karmali V. Rao A.S. Madara J.L. Science. 2000; 289: 1560-1563Crossref PubMed Scopus (744) Google Scholar). However, it is likely that the proinflammatory potential of invaded IEC does not simply reflect NF-κB activation. The transcriptional pattern of these cells is likely to encompass a complex combination of activation and repression of several transcriptional systems. NF-κB dominates among these systems, as reflected by the release of IL-8, a common denominator to a variety of invasive microorganisms and epithelial cell types (19Eckman L. Kagnoff M.F. Fierer J. Infect. Immun. 1995; 61: 4569-4574Crossref Google Scholar). In vivo, the production of IL-8 is largely associated with infected IEC, as demonstrated in the rabbit-ligated loop model of shigellosis. In this model, neutralization of IL-8 causes massive decrease of PMN recruitment, resulting in protection of the epithelium against inflammatory destruction, but also in uncontrolled growth of bacteria in the lamina propria (20Sansonetti P.J. Arondel J. Huerre M. Harada A. Matsushima K. Infect. Immun. 1999; 67: 1471-1480Crossref PubMed Google Scholar). Therefore, in shigellosis, the innate immune response corresponds to a balance between bacterial eradication and destruction of the mucosa. IL-8 produced by IEC plays a major role in this process, although the complexities and subtleties of transcriptional regulation leading to this particular profile are currently unknown and probably vary depending on the nature of the invasive microorganism and timing of the infectious process. In addition, with time, the epithelial response is likely to increasingly reflect a response to the proinflammatory cytokines that are massively released, such as TNF-α, which plays a major role in epithelial destruction in experimental shigellosis (21D'Hauteville H. Khan S. Maskell D.J. Kussak A. Weintraub A. Mathison J. Ulevitch R.J. Wuscher N. Parsot C. Sansonetti P.J. J. Immunol. 2002; 168: 5240-5251Crossref PubMed Scopus (114) Google Scholar). In addition, when bacteria reach subepithelial tissues, they encounter other cell populations, particularly resident macrophages and recruited monocytes that will impose their own profile of response, which is dominated by CD14/TLR4 recognition of Shigella lipopolysaccharide, as shown by the dramatic changes in mucosal response observed either upon CD14 neutralization (22Wenneras C. Ave P. Huerre M. Arondel J. Ulevitch R.J. Mathison J.C. Sansonetti P.J. J. Immunol. 2000; 164: 3214-3221Crossref PubMed Scopus (33) Google Scholar) or upon infection by a Shigella mutant that was genetically engineered to express a non-endotoxic lipid A (21D'Hauteville H. Khan S. Maskell D.J. Kussak A. Weintraub A. Mathison J. Ulevitch R.J. Wuscher N. Parsot C. Sansonetti P.J. J. Immunol. 2002; 168: 5240-5251Crossref PubMed Scopus (114) Google Scholar). To provide a detailed analysis of the transcriptional response of IEC invaded by S. flexneri (i.e. 45 min to 4 h), we have applied the Affymetrix microarray technology. Thus, the transcriptome of the human colonic Caco-2 cell line was established upon its infection with strain M90T, which expresses an invasive phenotype, due to the presence of the 213-kb virulence plasmid (23Sansonetti P.J. Kopecko D.J. Formal S.B. Infect. Immun. 1982; 35: 852-860Crossref PubMed Google Scholar). The M90T-induced transcriptome was compared with the transcriptomes obtained by infecting Caco-2 cells with strain BS176, a non-invasive, plasmid-less derivative of M90T, or by exposing cells to TNF-α. These experiments demonstrate that the transcriptome of Shigella-invaded IEC reflects the invasive phenotype and is significantly different from that induced by TNF-α in that it is almost exclusively devoted to the recruitment, activation, and adherence of PMN. This observation opens the way to studying the extent of transcriptional regulation achieved by the Nod1 cascade, upon stimulation by intracellular Shigella, and suggests that virulence proteins of Shigella, particularly those that are secreted through the type III secretory apparatus, may “remodel” this basic transcriptome. Cell Culture—The human IEC line Caco-2 derived from a colonic carcinoma (24Rousset M. Biochimie (Paris). 1986; 68: 1035-1040Crossref PubMed Scopus (375) Google Scholar) was used in this study. Cells were grown in an incubator at 37 °C, 10% CO2, in Dulbecco's modified Eagle's medium supplemented with 10% decomplemented fetal calf serum, 1% non-essential amino acid, and antibiotics (penicillin-streptomycin, respectively, 100 units/ml and 100 μg/ml). Before infection with bacteria, cells were washed in Dulbecco's modified Eagle's medium without serum and incubated at 37 °C for 2 h in the same medium. Bacterial Strains and Infection—Two bacterial strains were used in this study: the wild-type Shigella flexneri 5a (M90T) that possesses the virulence plasmid and its plasmid-cured mutant BS176, which is non-invasive (23Sansonetti P.J. Kopecko D.J. Formal S.B. Infect. Immun. 1982; 35: 852-860Crossref PubMed Google Scholar). One isolated colony on Tris-buffered saline agar containing 0.01% Congo red (25Bahrani F.K. Sansonetti P.J. Parsot C. Infect. Immun. 1997; 65: 4005-4010Crossref PubMed Google Scholar) was seeded in 7 ml of Tris-buffered saline broth for overnight culture. Before cell infection, bacteria were diluted in fresh broth for 2 h to be harvested in exponential phase of growth. Caco-2 cells were grown in 10-cm-diameter Petri dishes. To obtain an efficient cell invasion, non-confluent Caco-2 cell cultures were infected with bacteria with a multiplicity of infection of 100 bacteria/cell. After a 15-min-centrifugation at 2,000 rpm, cells and bacteria were incubated for 45 min and then washed three times in Dulbecco's modified Eagle's medium and reincubated for 75 or 195 min with 50 μg/ml gentamicin to kill extracellular bacteria. As confirmed by Giemsa staining, more than 70% of the cells were regularly infected. Preparation of mRNA and Hybridization on Affymetrix Chips—Following washing in cold phosphate-buffered saline, cells were lysed, and the total RNA was extracted by RNeasy Mini kit (Qiagen, Valencia, CA). Integrity and purity of RNA were checked by spectrophotometry and capillary electrophoresis, using the Bioanalyzer 2100 and RNA 6000 LabChip kit from Agilent Technologies (Palo Alto, CA). cDNA were synthesized using Superscript Choice system (Invitrogen). Biotin-labeled-cRNA was then synthesized with the Enzo BioArray High Yield RNA transcript labeling kit (Enzo Biochem, New York, NY). After purification with Rneasy columns (Qiagen), 12.5 μg of fragmented cRNA were hybridized to an HG-U95Av2 array (Affymetrix), and the chips were automatically washed and stained with streptavidine-phy-coerythrin using a fluidics station. Finally, the arrays were scanned at 570 nm with a resolution of 3 μm/pixel, using a GeneArray scanner from Agilent Technologies. Analysis of Results—In the Affymetrix technology (26Lipshutz R.J. Fodor S.P. Gingeras T.R. Lockhart D.J. Nat. Genet. 1999; 21: 20-24Crossref PubMed Scopus (1847) Google Scholar), 25-mer oligonucleotides are directly synthesized on the glass slides. For each gene sequence, 16–20 different oligonucleotides are present, and for each oligonucleotide, the perfect match is the exact homology of the gene selected, whereas for the mismatch, the nucleotide in position 13 is wrong. For the analysis, two versions of MicroArray Suite from Affymetrix were used, MAS4.0 (27Lockhart D.J. Dong H. Byrne M.C. Follettie M.T. Gallo M.V. Chee M.S. Mittmann M. Wang C. Kobayashi M. Horton H. Brown E.L. Nat. Biotechnol. 1996; 14: 1675-1680Crossref PubMed Scopus (2786) Google Scholar) and MAS5.0 (28Hubbell E. Liu W.-M. Mei R. Bioinformatics (Oxf.). 2002; 18: 1585-1592Crossref PubMed Scopus (492) Google Scholar). Expression algorithms compute two main metrics for each transcript, the absolute or detection call (present, marginal, or absent) determining whether the transcript is reliably detected by the probe array and the average difference or signal reflecting the relative level of expression of the transcript. In the first experiments, the fluorescence obtained was analyzed using MAS4.0 software, based on empirical algorithms. A normalization factor (the scaling factor) was applied, and then after background substraction and statistical comparison of the hybridations between perfect matches and mismatches, the presence or absence of the gene was provided, thus constituting the absolute call (present, marginal, or absent). Then the average difference, directly related to the expression of the transcripts, was determined. The comparative analysis, also performed by MAS, allowed the comparison between two samples, one used as baseline (in our case, the non-infected) and the experiment (infected with invasive or non-invasive bacteria). This analysis indicated whether there was a change in gene expression between the two samples. This was provided as the change call (increase, marginal increase, decrease, marginal decrease, or no change) and also by the -fold change (between the signal of the experimental sample and of the baseline sample). With MAS 5.0, the empirical algorithms are replaced by statistical algorithms; the major difference between the two versions of the software is that in the comparative analysis, the -fold change is shown as a logarithmic scale. The clustering analysis with Data Mining Tool (DMT version 3.0) of the microarray experiment allowed the identification of gene expression patterns. One of the methods used was the correlation coefficient clustering algorithm, which finds probe set patterns that have similar shapes. Three steps are successively performed for finding clusters of similar probe set patterns: (i) filtering to remove patterns mostly related to noise, (ii) seeding to define the expression patterns of the clusters using a nearest neighbor approach, and (iii) clustering to group patterns that are close to the cluster shape define in the previous step. Detection of Protein Expression—Caco-2 cells were infected with Shigella, as described above, in 12-well culture plates. At different time points (60, 120, 240, and 360 min), culture media were centrifuged (1,500 rpm, 10 min), and enzyme-linked immunosorbent assay tests for immunodetection of IL-8 and CXCL1 chemokines were performed, following the supplier's recommendations (Quantikine®, R&D Systems, Inc., Minneapolis, MN). Chemokine concentrations were determined from the standard curve provided in the detection kit. The experiments were performed twice in duplicate. Patterns of Gene Expression in Non-infected and Shigella-infected Human Colonic Caco-2 Cells—To enable evaluation of the reproducibility among different experiments, 4–5 independent microarray hybridization experiments were performed either on non-infected cells or on cells infected by the wild-type strain M90T or on cells infected by its non-invasive plasmid-less derivative, BS176. Only half of the12,000 human genes displayed on the Affymetrix U95A chip were expressed by Caco-2 cells, based on the absolute calls determined by MAS software provided by Affymetrix for data analysis. The method of analysis by correlation coefficient clustering, using the nearest neighbor approach, provided by DMT allowed us to visualize the gene expression patterns by creating plots. Using this method, 18 different clusters were created, and the two most representative plots were designated Cluster 1 and Cluster 2, as shown in Fig. 1. Cluster 1 encompasses genes whose transcription was up-regulated by both M90T and BS176, and Cluster 2 encompasses genes whose transcription was up-regulated by M90T, but not by BS176, i.e. genes whose up-regulation reflected the IEC response to the Shigella invasive phenotype. The number of genes in each cluster was the result of the three steps involved in the correlation coefficient clustering analysis as described under “Experimental Procedures.” It should be noted that the other analysis performed, comparative analysis with MAS or T-test analysis provided by DMT, gives the same regulated genes. As we cannot shown in this manuscript all the methods used to analyze the data presented here, we only shown the clustering analysis because it is the most convenient to visualize distinct gene expression pattern. Moreover, no significant down-regulation of gene transcription was observed in this series of experiments. Cluster 1, Genes Up-regulated during a 2-h Infection with either M90T or BS176 —We identified a total of 240 genes whose transcription was up-regulated, regardless of the expression of the invasive phenotype by Shigella. Considering that a plasmid-less Shigella is devoid of any specific pathogenic factor (i.e. no adherence-invasive capacity, no protein secretion) and that the species has lost expression of flagella, a major stimulus eliciting a proinflammatory program in IEC via TLR5 recognition (11Hayashi F. Smith K.D. Ozinsky A. Hawn T.R. Yi E.C. Goodlett D.R. Eng J.K. Akira S. Underhill D.M. Aderem A. Nature. 2001; 410: 1099-1103Crossref PubMed Scopus (2742) Google Scholar), the cell response might reflect (i) the recognition of bacteria-associated molecular patterns (i.e. lipopolysaccharide, peptidoglycan, lipoproteins) as well as (ii) the stress response to metabolic products released by infecting bacteria and to the conditions of competition for essential nutrients. Table I shows genes whose ratio of transcriptional up-regulation by Shigella infection, normalized to the background expression in non-infected cells, was over 1.5 with at least one of the two infecting organisms and with a significant absolute call. This ratio was computed from results obtained in four independent samples of cells infected by M90T or BS176 and five independent samples of non-infected cells. Data presentation in Fig. 1 has been organized according to sets of genes reflecting similar functions. The complete list of the cluster, like the other tables shown in this study, may be found as supplemental data. The complete results are available upon request.Table IGenes up-regulated during infection of Caco-2 cells with both the invasive and non-invasive strains of S. flexneriCategory of genesAccession numberaThese accession numbers are GenBank™ accession numbers.Description of genes-Fold increaseBS176/NIM90T/NIbAs indicated in the text, the numbers shown are ratios between either the average signal computed from four different samples of cells infected by invasive strain M90T, or four different samples of cells infected by non-invasive strain BS176, over the average signal computed from five different samples of non-infected (control) cells (NI).DetoxificationK03191Cytochrome P-1-450 (TCDD-inducible)8.127.13X02612Cytochrome P(1)-4507.307.36X02612Cytochrome P(1)-4506.575.66U03688Dioxin-inducible cytochrome P4503.443.17U03688Dioxin-inducible cytochrome P4503.303.04U07919Aldehyde dehydrogenase 65.274.70ApoptosisM30704Amphiregulin1.581.54AF005775Clarp 21.731.93X70340Transforming growth factor α1.461.69PhosphataseM25393Protein tyrosine phosphatase1.591.21ReceptorX77777Intestinal VIP receptor related protein1.742.30U68019Mad protein homolog1.752.01U68019Mad protein homolog1.741.82GTPase-activating proteinU90920PTPL1-associated RhoGAP1.661.73Cellular cycleAF091433Cyclin E21.531.63DNAAF084513DNA repair exonuclease (REC1)1.511.41D83702Photolyase1.971.83TranscriptionAF078096Forkhead/winged helix-like transcription factor 7 (FKHL7)1.511.41L40904Peroxisome proliferator activated receptor γ1.621.41OthersM26683Interferon γ treatment inducible2.292.72AF099935MDC-3.13 isoform 21.461.67AL049389DKFZp586O01182.472.38AL049933DKFZp564K12161.701.81W28830Homo sapiens cDNA1.601.46AL035447Clone 1183I211.571.50a These accession numbers are GenBank™ accession numbers.b As indicated in the text, the numbers shown are ratios between either the average signal computed from four different samples of cells infected by invasive strain M90T, or four different samples of cells infected by non-invasive strain BS176, over the average signal computed from five different samples of non-infected (control) cells (NI). Open table in a new tab The pattern of gene expression was dominated by up-regulation of genes involved in cell detoxification processes, such as several isoforms of cytochrome P-450 (CYP) with ratios of up-regulation between 3- and 8-fold and aldehyde-dehydrogenase (∼5-fold) (29Sophos N.A. Pappa A. Ziegler T.L. Vasiliou V. Chem. Biol. Interact. 2001; 130–132: 323-337Crossref PubMed Scopus (64) Google Scholar). In addition, genes regulating cell survival and proliferation were also induced, such as those encoding the caspase-like apoptosis-regulating protein (Clarp, Ref. 30Inohara N. Koseki T. Hu Y. Chen S. Nunez G. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: 10717-10722Crossref PubMed Scopus (278) Google Scholar), amphiregulin (31Piepkorn M. Pittelkow M.R. Cook P.W. J. Invest. Derm. 1998; 111: 715-721Abstract Full Text Full Text PDF PubMed Scopus (121) Google Scholar, 32Damstrup L. Kuwada S.A. Dempsey P.J. Brown C.L. Hawkey C.J. Poulsen H.S. Wiley H.S. Coffey Jr., R.J. Br. J. Cancer. 1999; 80: 1012-1019Crossref PubMed Scopus (57) Google Scholar) and TGF-α (33Jiang D. Liang J. Humphrey L.E. Yang H. Brattain N.G. J. Cell. Physiol. 1998; 175: 174-183Crossref PubMed Scopus (15) Google Scholar), two EGF-related growth factors produced by epithelial cells that function as autocrine/paracrine factors activating cell proliferation. Both molecules are ligands for the EGF receptor (31Piepkorn M. Pittelkow M.R. Cook P.W. J. Invest. Derm. 1998; 111: 715-721Abstract Full Text Full Text PDF PubMed Scopus (121) Google Scholar). Up-regulation of the VIP receptor gene (34Couvineau A. Rouyer-Fessard C. Darmoul D. Maoret J.J. Carrero I. Ogier-Denis O. Laburthe M. Biochem. Biophys. Res. Commun. 1994; 200: 769-776Crossref PubMed Scopus (149) Google Scholar) may follow this logic of a protective program since VIP acts as a neuroendocrine mediator that not only stimulates water and electrolyte secretion in the gut but also promotes growth and proliferation of normal and malignant cells. Increased transcription of DNA repair genes, such as exonuclease Rec1 (35Schmutte C. Sadoff M.M. Kang-Sup S. Acharya S. Fishel R. J. Biol. Chem. 2001; 276: 33011-33018Abstract Full Text Full Text PDF PubMed Scopus (133) Google Scholar) and photolyase (36Thoma F. EMBO J. 1999; 18: 6585-6598Crossref PubMed Google Scholar), probably also reflects this protective program. Concerning inflammation, it is interesting to note that within the 2-h period of infection, no evidence for induction of a proinflammatory program was observed, with the exception of the gene encoding IFN-γ treatment-inducible protein (37Fan X.D. Stark G.R. Bloom B.R. Mol. Cell Biol. 1989; 9: 1922-1928Crossref PubMed Scopus (33) Google Scholar). On the other hand, transcriptional induction of the peroxisome proliferator-activated receptor-γ is a very stimulating observation since this nuclear receptor has been shown to elicit a potent anti-inflammatory signal (38Desreumaux P. Dubuquoy L. Nutten S. Peuchmaur M. Englaro W. Schoonjans K. Derijard B. Desvergnes B. Wahli W. Chambon P. Leibowitz M.D. Colombel J.-F. Auwerx J. J. Exp. Med. 2001; 193: 827-838Crossref PubMed Scopus (393) Google Scholar). In summary, BS176 induces a transcriptome reflecting a program of cell protection and survival and possibly of antiinflammation. This basic program was also induced by M90T, although as shown below, a proinflammatory program reflecting expression of the invasive phenotype quickly prevailed. Cluster 2, Genes Up-regulated during a 2-h Infection with M90T—Following a 2-h infection, we identified a total of 72 genes whose increased transcription was specifically related to expression of the invasive phenotype by Shigella. Table II reports genes whose transcriptional induction over non-infected cells showed a ratio superior to 1.5.Table IIGenes up-regulated during infection of Caco-2 cells with M90T, the invasive strain of S. flexnerCategory of genesAccession numberaThese accession numbers are GenBank™" @default.
• W2034504117 created "2016-06-24" @default.
• W2034504117 creator A5007150926 @default.
• W2034504117 creator A5068346044 @default.
• W2034504117 creator A5069666784 @default.
• W2034504117 date "2003-09-01" @default.
• W2034504117 modified "2023-09-27" @default.
• W2034504117 title "The Invasive Phenotype of Shigella flexneri Directs a Distinct Gene Expression Pattern in the Human Intestinal Epithelial Cell Line Caco-2" @default.
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