The impact of hypoxia on intestinal epithelial cell functions: consequences for invasion by bacterial pathogens
© Zeitouni et al. 2016
Received: 1 December 2015
Accepted: 13 March 2016
Published: 22 March 2016
The maintenance of oxygen homeostasis in human tissues is mediated by several cellular adaptations in response to low-oxygen stress, called hypoxia. A decrease in tissue oxygen levels is initially counteracted by increasing local blood flow to overcome diminished oxygenation and avoid hypoxic stress. However, studies have shown that the physiological oxygen concentrations in several tissues are much lower than atmospheric (normoxic) conditions, and the oxygen supply is finely regulated in individual cell types. The gastrointestinal tract has been described to subsist in a state of physiologically low oxygen level and is thus depicted as a tissue in the state of constant low-grade inflammation. The intestinal epithelial cell layer plays a vital role in the immune response to inflammation and infections that occur within the intestinal tissue and is involved in many of the adaptation responses to hypoxic stress. This is especially relevant in the context of inflammatory disorders, such as inflammatory bowel disease (IBD). Therefore, this review aims to describe the intestinal epithelial cellular response to hypoxia and the consequences for host interactions with invading gastrointestinal bacterial pathogens.
KeywordsOxygen Invasion β1 integrin Infection HIF-1α Intestine
Physiological oxygen concentrations
Hypoxia during infections and inflammation
Hypoxic stress, that occurs when cellular oxygen demand is higher than its supply, is a commonplace in tissues faced with infection and inflammation [7, 8]. There are many factors that result in this oxygen deficit, including the demands of innate immune cells, such as neutrophils and macrophages that are recruited to the site of infection as well as those of invading pathogens that also consume oxygen [9, 10]. These increased oxygen demands, in addition to the requirements of the resident cells of the infected tissue, can cause a severe drop in available oxygen levels, resulting in a state of hypoxia. Infiltrating neutrophils play an important role in the host response to inflammation and result in depletion of oxygen, transcriptional changes, and aberrant vascularization . Recruited polymorphonuclear neutrophils (PMNs) rapidly generate reactive oxygen species, mediated by a powerful oxidative burst, thus immensely increasing oxygen consumption. Activated PMNs elicit an almost 50-fold increase in oxygen demands and thus contribute to the hypoxic conditions in the inflamed tissue [7, 8].
The human gut is host to a large number of commensal bacteria that inhabit the lumen and epithelial mucosa of the lower intestine and has developed productive relationships with its microbiota; however, it remains highly vigilant against invading pathogens . In cases when the balance of the normal flora is upset, or if the intestinal barrier is breached, infection can occur from invading pathogens or from overgrowth of endogenous pathogens . Indeed, invasive enteropathogenic bacteria, including Salmonella, Shigella, and Yersinia, cause considerable damage to the mucosal layer and the intestinal epithelial cells as well as the lamina propria . Enterocolitis, as the most common presentation of Yersinia enterocolitica infection, occurs primarily in young children, with a mean age of 24 months. The incubation period is 4–6 days, typically with a range of 1–14 days. Most cases are self-limited. However, concomitant bacteremia may occur in 20–30 % of infants younger than 3 months . Besides the physical and structural damage that occur during those intestinal infections, many of the intestinal pathogens induce the expression of inflammatory and chemoattractive cytokines that collectively raise an immune response . Therefore, it is a point of interest to investigate the fate of the epithelial layer of the intestinal tissue during a bacterial infection under hypoxia and whether the cellular adaptation mechanisms offer the host any protective or defensive advantages. Understanding the protective host response under hypoxia might finally help to develop new prophylactic or therapeutic strategies that might be supportive for the host during cellular stress response.
Transcriptional response to hypoxia
Living organisms have developed rather efficient mechanisms to maintain cellular homeostasis and to circumvent stressful conditions. At the cellular level, many genes are involved in the adaptation processes either in a regulatory capacity or in a functional manner. One very well-characterized regulator of the cellular response to low oxygen levels is the transcription factor hypoxia inducible factor 1 (HIF-1). HIF-1 has been found to bind to and induce the expression of several genes whose products promote erythropoiesis and angiogenesis and are involved in glucose transport and metabolism, thus initiating the cellular adaptation response to hypoxic stress [15, 16]. HIF-1 is a transcription factor consisting of two subunits: the oxygen regulated alpha (α) and a constitutively expressed beta (β) subunit, also known as the aryl hydrocarbon receptor nuclear translocator (ARNT) . HIF-1α protein is a global regulator of the energy homeostasis and cellular adaptation to hypoxia, and its stability is tightly regulated by the cellular oxygen concentration . During conditions of adequate oxygenation, or normoxia, HIF-1α is rapidly degraded by binding of the von Hippel-Lindau tumor suppressor protein (pVHL) that subsequently targets it for ubiquitination and proteosomal degradation . This process is mediated by oxygen- and iron-dependent prolyl hydroxylases (PHDs) that transfer a hydroxyl group onto two proline residues (P402 and P564) allowing for binding to pVHL . Under hypoxic conditions, HIF-1α rapidly accumulates due to the interruption of its degradation pathway by inhibition of the oxygen-dependent hydroxylation .
Several HIF-1 target genes have been shown to mediate a protective effect on the mucosal layer through the upregulation of CD55, ecto-50 nucleotidase, MUC-3, intestinal trefoil factor, and P-glycoprotein . This enhanced expression of barrier-protective genes may present an obstacle to invasive gastrointestinal bacteria that seek to invade by paracellular translocation across the epithelial layer, like Vibrio cholera and Clostridium difficile . Furthermore, nuclear factor-kappa B (NF-κB), a central regulator of innate immunity and inflammatory processes, is activated in hypoxia, both in vitro and in vivo . A complex connection exists between HIF-1 and NF-κB; both transcription factors have several target genes in common, and NF-κB activation can stabilize HIF-1α, yet HIF-1 can repress NF-κB activity during inflammation . However, studies have also implicated HIF-independent NF-kB-mediated pathways in the host response at sites of inflammation, where NF-kB is required for the maintenance of epithelial barrier integrity [8, 21]. Conditional deletion of NF-kB in intestinal epithelial cells in mice led to an increased susceptibility to colitis in a murine model . It has therefore been suggested that hypoxia regulates inflammatory responses through the activation of NFκB signaling pathway in a multi-factorial process . This hypoxia-mediated induction of inflammatory responses may provide a better defense against invading pathogens.
Cellular adaptation to hypoxia
Bacterial invasion mechanisms: trigger or zipper
Main gastrointestinal pathogens and their specific mode of entry
Internalization under hypoxia
Potential mechanism of hypoxia-induced changes
Signaling from Rac1 to Arp2/3 
Decreased receptor protein expression, reduced glycosylation and mislocalization in lipid rafts 
Ligase Hakai recruitment, clathrin endocytosis, and activation of Arp2/3 actin complex 
Elevated expression of barrier protection genes, more increased levels of E-cadherin 
Met (hepatocyte growth factor receptor)
Activation of Met and PI-3-kinase-mediated signaling 
Increased expression of growth factor receptors 
Mammalian factor FXYD3
Impairment of function of tight junctions 
Increased barrier protection, more stable adherens, and tight junctions 
Cdc42, Rac1, Rho
Activation of target, membrane ruffling 
Cytoskeleton rearrangements hinder membrane ruffling 
Salmonella (SipA, SipC)
Phosphatidylinositol 4,5-bisphosphate PtdIns (4,5) P2
Phosphoinositide signaling; membrane ruffling and formation of macropinosomes 
Changes in membrane lipid composition 
One region of the plasma membrane that poses great interest to host pathogen interactions is lipid rafts. Lipid rafts are ordered liquid domains rich in sphingolipids and cholesterol and segregated from less-ordered liquid domains composed of mainly unsaturated phospholipids . Cell signaling, intracellular membrane transport, cell adhesion, and host-pathogen interactions are among the cell processes regulated by lipid rafts . Therefore, any chemical and physical perturbations of plasma membrane structure or composition may have a dramatic effect on cellular processes that are associated with lipid rafts. In fact, hypoxic exposure leads to the selective remodeling of membrane lipids and proteins, more specifically to an increase in saturated fatty acid content due to the inability to perform β-oxidation in oxygen-limited conditions while amounts of phospholipids and free cholesterol remain unchanged . In alveolar cells, mild hypoxia results in a significant increase in the cholesterol to phospholipids ratio causing a decrease in membrane fluidity, with no significant increase in lipid peroxidation . This selective lipid enrichment and decrease in membrane fluidity under hypoxia is suggested as an adaptation response to regulate the function of membrane-bound proteins and their localization by decreasing endocytosis . Furthermore, when membrane composition is altered, membrane-associated proteins are also most likely affected. The protein marker of caveolae, caveolin 1 (Cav-1), reveals reduced levels in the lipid microdomains while the total content of this protein the membranes remains unchanged, thus indicating a redistribution within the membrane . These studies were performed in various types of cells, however, and not much is known about membrane alterations in intestinal epithelial cells. Considering that the main point of contact between pathogens and intestinal host cells is at the plasma membrane, it is possible that alterations in membrane-associated receptors may protect against bacterial invasion. Host β1 integrins, that are the main receptors for Y. enterocolitica, are lipid raft-associated proteins that require these platforms for clustering as well as recycling [37, 38]. In the absence of anchored and clustered receptors at the cell surface, due to hypoxia-mediated alterations, bacterial attachment and internalization may be greatly hindered, thus providing the host cells with protection against invading pathogens. In fact, we have shown a significant reduction in brush border membrane enrichment of β1 integrins under hypoxia, thus severely reducing Y. enterocolitica internalization into Caco-2 cells . Furthermore, studies have shown that after 5-h incubation under 1 % O2, phosphatidylinositol activity is increased in hepatoma cells . Since phosphatidylinositol is used by S. typhimurium to internalize into host cells, its accumulation under hypoxia may explain the increased pathogen entry . On the other hand, S. flexneri effectors deplete phosphatidylinositol from the plasma membrane in order to limit membrane cytoskeletal interactions and facilitate entry into host cells . An increase in membrane phosphatidylinositol levels may be the reason why Shigella entry into host cells is hindered under hypoxia .
Another key aspect of the cellular response to hypoxia is cytoskeletal adaptation. Studies have reported hypoxia-induced disorganization of the cytoskeletal network by disrupting F-actin filaments and by excessive cleavage of α-spectrin, an apical protein, that binds to the actin cytoskeleton and sodium transport proteins . Furthermore, hypoxia has been shown to have a distinct effect on epithelial cells by disrupting the actin cytoskeleton and tight junctions, by mislocalization of occludin and reduction of the zonula occludens 1 [42, 43]. Furthermore, hypoxia regulates the Rho guanosine triphosphatases (GTPases) that modulate the activity of actin-binding proteins, by inhibiting their isoprenylation and thus resulting in decreased actin polymerization and eventually in impaired endocytosis . Since many invasive pathogens, such as Shigella and Yersinia species, hijack the host cytoskeletal system in order to internalize into their target cells, any alterations in the cytoskeletal activity and structure can hinder this internalization process . Oxygen-dependent modifications of the host cytoskeleton also significantly affect the paracellular permeability, intracellular transport, and the general endocytic uptake of particles in alveolar epithelial cells . Since some of these bacteria are internalized into the intestinal epithelial cells via some form of endocytosis or membrane invagination, fragments of host plasma membrane will form the pathogen-containing compartments. Therefore, alterations in the host endocytic process caused by oxygen deficiency would also affect these compartments and ultimately influence intracellular bacterial survival .
Endoplasmic reticulum stress
The endoplasmic reticulum (ER) is responsible for protein translocation, folding, post-translational modifications, and finally, protein delivery to their proper target sites . Under stressful conditions such as inflammation or infection, ER homeostasis is disturbed, causing the accumulation of misfolded or unfolded proteins in the ER lumen and ultimately leading to the induction of the unfolded protein response (UPR) . The UPR consists of several steps, including (1) lowered protein biosynthesis and translocation into the ER, (2) increased expression of chaperones to aid in protein folding, (3) degradation of unfolded proteins, and finally, (4) apoptosis that eventually leads to pathogenic phenotypes . Hypoxia has been shown to induce ER stress and can lead to the initiation of UPR, which in turn increases the transcription of pro-angiogenic genes such as VEGF by enhancing HIF-1α activity .
The first barrier that microorganisms encounter in the intestine is a thick mucosal layer overlying the epithelial cells that provides protection against invading pathogens and other chemical or mechanical threats, composed mainly of glycoproteins called mucins . During infections, mucins are commonly associated with pathogen adherence, and both S. typhimurium and Y. enterocolitica virulent strains were shown to specifically bind to mucins in the intestinal tract [60, 61]. Mucin expression can be increased by various cues, such as exposure to microbes, pro-inflammatory cytokines, and resident macrophages, thus providing a link between innate mucosal immunity, and inflammatory responses . Increased expression of Muc 2, a major intestinal mucin, was shown to protect against infectious colitis by limiting Citrobacter rodentium translocation across the intestinal epithelial layer in mice . Interestingly, hypoxia increases the expression of Muc 1 and Muc 2 in a HIF-1α-dependent manner in renal and peritoneal tumors, respectively [63, 64]. Whether this hypoxia-mediated increase in mucins aids in the entrapment of invading pathogs or serves to strengthen the epithelial barrier remains unclear. Besides transcriptional regulation of mucins, alterations in mucin glycosylation have been shown to occur, thus affecting microbial adhesion and circumventing mucus degradation by microbes . As we have discussed in this review, hypoxia-induced ER stress can lead to alterations in glycosylation patterns, suggesting a potential role for hypoxia in mucin response to infections and their role in pathogen clearance.
Relevance in the context of inflammatory bowel diseases
The GI tract has been described to be in a state of constant, low-grade inflammation associated with hypoxia, with intestinal epithelial cells playing a pivotal role in mucosal immunity in response to this inflammation and in maintaining homeostasis . Chronic gastrointestinal inflammatory conditions, such as Crohn’s disease and ulcerative colitis, are characterized by exaggerated inflammatory responses to the luminal microbiome and are aggravated by the resulting epithelial barrier dysfunction .
Interestingly, HIF-1α was found to be highly expressed in epithelial cells from both Crohn’s disease and ulcerative colitis patients . The role of HIF-1α and its activated pathways was revealed to be a protective one, with suggested mechanisms that include improved barrier protection and prevention of epithelial cell apoptosis [21, 67]. Furthermore, conditional knockout of HIF-1α expression in intestinal epithelial cells exacerbated barrier injury and resulted in more severe symptoms in a murine colitis model . A similar aggravation in inflammatory damage was seen in C. difficile toxin-induced colitis in mice lacking intestinal epithelial HIF-1α . In contrast, increasing HIF-1α by pharmacological inhibition of its degradation substantially reduced the extent of injury caused by inflammatory damage in these colitis models [67, 68].
In light of increasing antibiotic resistance, novel approaches to treatment of infections are needed, and methods for boosting the host defense are currently being explored . Because of its implication in the hypoxia-induced modulation of the immune response, HIF-1α has been considered as a possible novel therapeutic target . Pharmacological manipulation of HIF-1α significantly improved the ability of keratinocytes to fight against skin infections . Treatment with a HIF-1α agonist boosts the innate immune response of the intestinal epithelium in a murine colitis model .
These data strongly suggest that HIF-1α is a promising candidate for use as a therapeutic agent for the treatment of several pathological conditions. The ability of HIF-1α to boost the innate immune cells is a very attractive feature that can be effective in the treatment of multi-drug resistant bacterial infections or in immunocompromised patients . Since the pharmacological stabilization of HIF-1α results in the increase of a number of antimicrobial host agents, the chances for the development of bacterial resistance are greatly diminished .
Ultimately, it is important to emphasize the relevance of studying hypoxia and the pathways involved in the adaptation to oxygen stress in the context of gastrointestinal perturbations and the host cell endeavors to maintain homeostasis.
This work was partially supported by DFG grant KO 3552/4-1 (MvK-B); NZ was funded by the German Academic Exchange Service (DAAD), and SC was funded by the Mahanakorn University of Technology, Thailand.
Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
- Carreau A, El Hafny-Rahbi B, Matejuk A, Grillon C, Kieda C (2011) Why is the partial oxygen pressure of human tissues a crucial parameter? Small molecules and hypoxia. J Cell Mol Med 15:1239–1253. doi:10.1111/j.1582-4934.2011.01258.x View ArticlePubMedPubMed CentralGoogle Scholar
- Semenza GL (2012) Hypoxia-inducible factors in physiology and medicine. Cell 148:399–408. doi:10.1016/j.cell.2012.01.021 View ArticlePubMedPubMed CentralGoogle Scholar
- Guzy RD, Schumacker PT (2006) Oxygen sensing by mitochondria at complex III: the paradox of increased reactive oxygen species during hypoxia. Exp Physiol 91:807–819. doi:10.1113/expphysiol.2006.033506 View ArticlePubMedGoogle Scholar
- Taylor CT, Colgan SP (2007) Hypoxia and gastrointestinal disease. J Mol Med 85:1295–1300. doi:10.1007/s00109-007-0277-z View ArticlePubMedGoogle Scholar
- Fisher EM, Khan M, Salisbury R, Kuppusamy P (2013) Noninvasive monitoring of small intestinal oxygen in a rat model of chronic mesenteric ischemia. Cell Biochem Biophys 67:451–9. doi:10.1007/s12013-013-9611-y View ArticlePubMedGoogle Scholar
- Zeitouni NE, Fandrey J, Naim HY, von Köckritz-Blickwede M (2015) Measuring oxygen levels in Caco-2 cultures. Hypoxia 3:53–66. doi:10.2147/HP.S85625 Google Scholar
- Glover LE, Colgan SP (2011) Hypoxia and metabolic factors that influence inflammatory bowel disease pathogenesis. Gastroenterology 140:1748–1755. doi:10.1053/j.gastro.2011.01.056 View ArticlePubMedPubMed CentralGoogle Scholar
- Colgan SP, Curtis VF, Campbell EL (2013) The inflammatory tissue microenvironment in IBD. Inflamm Bowel Dis 19:2238–44. doi:10.1097/MIB.0b013e31828dcaaf View ArticlePubMedPubMed CentralGoogle Scholar
- Colgan SP, Taylor CT (2010) Hypoxia: an alarm signal during intestinal inflammation. Nat Rev Gastroenterol Hepatol 7:281–7. doi:10.1038/nrgastro.2010.39 View ArticlePubMedPubMed CentralGoogle Scholar
- Campbell EL, Bruyninckx WJ, Kelly CJ, Glover LE, McNamee EN, Bowers BE, Bayless AJ, Scully M, Saeedi BJ, Golden-Mason L, Ehrentraut SF, Curtis VF, Burgess A, Garvey JF, Sorensen A, Nemenoff R, Jedlicka P, Taylor CT, Kominsky DJ, Colgan SP (2014) Transmigrating neutrophils shape the mucosal microenvironment through localized oxygen depletion to influence resolution of inflammation. Immunity 40:66–77. doi:10.1016/j.immuni.2013.11.020 View ArticlePubMedPubMed CentralGoogle Scholar
- Melican K, Boekel J, Månsson LE, Sandoval RM, Tanner G a G a, Källskog Ö, Palm F, Molitoris B a, Richter-Dahlfors A (2008) Bacterial infection-mediated mucosal signalling induces local renal ischaemia as a defence against sepsis. Cell Microbiol 10:1987–1998. doi:10.1111/j.1462-5822.2008.01182.x View ArticlePubMedGoogle Scholar
- Gorbach SL (1996) Microbiology of the gastrointestinal tractGoogle Scholar
- Bottone EJ, Gullans CR, Sierra MF (1987) Disease spectrum of Yersinia enterocolitica serogroup 0:3, the predominant cause of human infection in New York City. Contrib Microbiol Immunol 9:56–60PubMedGoogle Scholar
- Neish AS (2002) The gut microflora and intestinal epithelial cells: a continuing dialogue. Microbes Infect 4:309–317. doi:10.1016/S1286-4579(02)01543-5 View ArticlePubMedGoogle Scholar
- Wang GL, Semenza GL (1993) General involvement of hypoxia-inducible factor 1 in transcriptional response to hypoxia. Proc Natl Acad Sci U S A 90:4304–4308. doi:10.1073/pnas.90.9.4304 View ArticlePubMedPubMed CentralGoogle Scholar
- Greijer A, van der Groep P, Kemming D, Shvarts A, Semenza G, Meijer G, van de Wiel M, Belien J, van Diest P, van der Wall E (2005) Up-regulation of gene expression by hypoxia is mediated predominantly by hypoxia-inducible factor 1 (HIF-1). J Pathol 206:291–304. doi:10.1002/path.1778 View ArticlePubMedGoogle Scholar
- Semenza GL, Wang GL (1992) A nuclear factor induced by hypoxia via de novo protein synthesis binds to the human erythropoietin gene enhancer at a site required for transcriptional activation. Mol Cell Biol 12:5447–5454. doi:10.1128/MCB.12.12.5447.Updated View ArticlePubMedPubMed CentralGoogle Scholar
- Wang GL, Jiang BH, Rue E a, Semenza GL (1995) Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension. Proc Natl Acad Sci U S A 92:5510–5514. doi:10.1073/pnas.92.12.5510 View ArticlePubMedPubMed CentralGoogle Scholar
- Lee J-W, Bae S-H, Jeong J-W, Kim S-H, Kim K-W (2004) Hypoxia-inducible factor (HIF-1) alpha: its protein stability and biological functions. Exp Mol Med 36:1–12. doi:10.1038/emm.2004.1 View ArticlePubMedGoogle Scholar
- Maxwell PH, Wiesener MS, Chang GW, Clifford SC, Vaux EC, Cockman ME, Wykoff CC, Pugh CW, Maher ER, Ratcliffe PJ (1999) The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis. Nature 399:271–275. doi:10.1038/20459 View ArticlePubMedGoogle Scholar
- Biddlestone J, Bandarra D, Rocha S (2015) The role of hypoxia in inflammatory disease (review). Int J Mol Med 35:859–869. doi:10.3892/ijmm.2015.2079 PubMedPubMed CentralGoogle Scholar
- Balkovetz DF, Katz J (2003) Bacterial invasion by a paracellular route: divide and conquer. Microbes Infect 5:613–619. doi:10.1016/S1286-4579(03)00089-3 View ArticlePubMedGoogle Scholar
- Koong a C, Chen EY, Giaccia a J (1994) Hypoxia causes the activation of nuclear factor kappa B through the phosphorylation of I kappa B alpha on tyrosine residues. Cancer Res 54:1425–1430PubMedGoogle Scholar
- Zaph C, Troy AE, Taylor BC, Berman-Booty LD, Guild KJ, Du Y, Yost E a, Gruber AD, May MJ, Greten FR, Eckmann L, Karin M, Artis D (2007) Epithelial-cell-intrinsic IKK-beta expression regulates intestinal immune homeostasis. Nature 446:552–556. doi:10.1038/nature05590 View ArticlePubMedGoogle Scholar
- Taylor CT, Cummins EP (2009) The role of NF-κB in hypoxia-induced gene expression. Ann N Y Acad Sci 1177:178–184. doi:10.1111/j.1749-6632.2009.05024.x View ArticlePubMedGoogle Scholar
- Alonso A, Del Portillo FG (2004) Hijacking of eukaryotic functions by intracellular bacterial pathogens. Int Microbiol 7:181–191PubMedGoogle Scholar
- Dos Reis RS, Horn F (2010) Enteropathogenic Escherichia coli, Samonella, Shigella and Yersinia: cellular aspects of host-bacteria interactions in enteric diseases. Gut Pathog 2:8. doi:10.1186/1757-4749-2-8 View ArticlePubMedPubMed CentralGoogle Scholar
- Stoodley BJ, Thom BT (1970) Observations on the intestinal carriage of Pseudomonas aeruginosa. J Med Microbiol 3:367–75. doi:10.1099/00222615-3-3-367 View ArticlePubMedGoogle Scholar
- Okuda J, Hayashi N, Okamoto M, Sawada S, Minagawa S, Yano Y, Gotoh N (2010) Translocation of Pseudomonas aeruginosa from the intestinal tract is mediated by the binding of ExoS to an Na, K-ATPase regulator, FXYD3. Infect Immun 78:4511–22. doi:10.1128/IAI.00428-10 View ArticlePubMedPubMed CentralGoogle Scholar
- Lima CBC, Dos Santos SA, De Andrade Junior DR (2013) Hypoxic stress, hepatocytes and CACO-2 viability and susceptibility to Shigella flexneri invasion. Rev Inst Med Trop Sao Paulo 55:341–346. doi:10.1590/S0036-46652013000500008 View ArticlePubMedPubMed CentralGoogle Scholar
- Schaible B, McClean S, Selfridge A, Broquet A, Asehnoune K, Taylor CT, Schaffer K (2013) Hypoxia modulates infection of epithelial cells by pseudomonas aeruginosa. PLoS One 8:1–11. doi:10.1371/journal.pone.0056491 Google Scholar
- Wells CL, VandeWesterlo E, Jechorek RP, Erlandsen SL (1996) Effect of hypoxia on enterocyte endocytosis of enteric bacteria. Crit Care Med 24:985–91View ArticlePubMedGoogle Scholar
- Lindner R, Naim HY (2009) Domains in biological membranes. Exp Cell Res 315:2871–2878. doi:10.1016/j.yexcr.2009.07.020 View ArticlePubMedGoogle Scholar
- Lafont F, van der Goot FG (2005) Bacterial invasion via lipid rafts. Cell Microbiol 7:613–620. doi:10.1111/j.1462-5822.2005.00515.x View ArticlePubMedGoogle Scholar
- Ledoux S, Runembert I, Koumanov K, Michel JB, Trugnan G, Friedlander G (2003) Hypoxia enhances Ecto-5′-nucleotidase activity and cell surface expression in endothelial cells: role of membrane lipids. Circ Res 92:848–855. doi:10.1161/01.RES.0000069022.95401.FE View ArticlePubMedGoogle Scholar
- Botto L, Beretta E, Bulbarelli A, Rivolta I, Lettiero B, Leone BE, Miserocchi G, Palestini P (2008) Hypoxia-induced modifications in plasma membranes and lipid microdomains in A549 cells and primary human alveolar cells. J Cell Biochem 105:503–513. doi:10.1002/jcb.21850 View ArticlePubMedGoogle Scholar
- Isberg RR, Leong JM (1990) Multiple beta 1 chain integrins are receptors for invasin, a protein that promotes bacterial penetration into mammalian cells. Cell 60:861–871. doi:10.1016/0092-8674(90)90099-Z View ArticlePubMedGoogle Scholar
- Deuretzbacher A, Czymmeck N, Reimer R, Trulzsch K, Gaus K, Hohenberg H, Heesemann J, Aepfelbacher M, Ruckdeschel K (2009) B1 Integrin-dependent engulfment of Yersinia enterocolitica by macrophages is coupled to the activation of autophagy and suppressed by type III protein secretion. J Immunol 183:5847–5860. doi:10.4049/jimmunol.0804242 View ArticlePubMedGoogle Scholar
- Zeitouni NE, Dersch P, Naim HY, von Köckritz-Blickwede M (2016) Hypoxia decreases invasin-mediated Yersinia enterocolitica internalization into Caco-2 cells. PLoS One 11:e0146103. doi:10.1371/journal.pone.0146103 View ArticlePubMedPubMed CentralGoogle Scholar
- Mottet D, Dumont V, Deccache Y, Demazy C, Ninane N, Raes M, Michiels C (2003) Regulation of hypoxia-inducible factor-1alpha protein level during hypoxic conditions by the phosphatidylinositol 3-kinase/Akt/glycogen synthase kinase 3beta pathway in HepG2 cells. J Biol Chem 278:31277–85. doi:10.1074/jbc.M300763200 View ArticlePubMedGoogle Scholar
- Brumell JH, Grinstein S (2003) Role of lipid-mediated signal transduction in bacterial internalization. Cell Microbiol 5:287–297. doi:10.1046/j.1462-5822.2003.00273.x View ArticlePubMedGoogle Scholar
- Bouvry D, Planès C, Malbert-Colas L, Escabasse V, Clerici C (2006) Hypoxia-induced cytoskeleton disruption in alveolar epithelial cells. Am J Respir Cell Mol Biol 35:519–527. doi:10.1165/rcmb.2005-0478OC View ArticlePubMedGoogle Scholar
- Molitoris BA, Dahl R, Hosford M (1996) Cellular ATP depletion induces disruption of the spectrin cytoskeletal network. Am J Physiol Ren Physiol 271:F790–798Google Scholar
- Takeuchi A (1967) Electron microscope studies of experimental Salmonella infection. I. Penetration into the intestinal epithelium by Salmonella typhimurium. Am J Pathol 50:109–136PubMedPubMed CentralGoogle Scholar
- Ron D, Walter P (2007) Signal integration in the endoplasmic reticulum unfolded protein response. Nat Rev Mol Cell Biol 8:519–29. doi:10.1038/nrm2199 View ArticlePubMedGoogle Scholar
- Pereira ER, Frudd K, Awad W, Hendershot LM (2014) Endoplasmic reticulum (ER) stress and hypoxia response pathways interact to potentiate hypoxia-inducible factor 1 (HIF-1) transcriptional activity on targets like vascular endothelial growth factor (VEGF). J Biol Chem 289:3352–3364. doi:10.1074/jbc.M113.507194 View ArticlePubMedPubMed CentralGoogle Scholar
- Lodish H, Berk A, Zipursky SL E Al, Lodish H, Berk A, Zipursky SL, Matsudaira P, Baltimore D, Darnell J (2000) Protein glycosylation in the ER and golgi complex. Mol Cell Biol. doi:http://www.ncbi.nlm.nih.gov/books/NBK21744/. Accessed 10 Nov 2015
- Jacob R, Naim HY (2001) Apical membrane proteins are transported in distinct vesicular carriers. Curr Biol 11:1444–1450. doi:10.1016/S0960-9822(01)00446-8 View ArticlePubMedGoogle Scholar
- Kim LT, Ishihara S, Lee CC, Akiyama SK, Yamada KM, Grinnell F (1992) Altered glycosylation and cell surface expression of beta 1 integrin receptors during keratinocyte activation. J Cell Sci 103(Pt 3):743–753PubMedGoogle Scholar
- Aoyama K, Ozaki Y, Nakanishi T, Ogasawara MS, Ikuta K, Aoki K, Blomgren K, Suzumori K (2004) Cleavage of integrin by mu-calpain during hypoxia in human endometrial cells. Am J Reprod Immunol 52:362–369View ArticlePubMedGoogle Scholar
- Zuk A, Bonventre JV, Brown D, Matlin KS (1998) Polarity, integrin, and extracellular matrix dynamics in the postischemic rat kidney. Am J Physiol 275:C711–C731PubMedGoogle Scholar
- Rana MK, Srivastava J, Yang M, Chen CS, Barber DL (2015) Hypoxia increases the abundance but not the assembly of extracellular fibronectin during epithelial cell transdifferentiation. J Cell Sci 128:1083–1089. doi:10.1242/jcs.155036 View ArticlePubMedPubMed CentralGoogle Scholar
- Cossart P, Pizarro-Cerda J, Lecuit M (2003) Invasion of mammalian cells by Listeria monocytogenes: functional mimicry to subvert cellular functions. Trends Cell Biol 13:23–31. doi:10.1016/S0962-8924(02)00006-5 View ArticlePubMedGoogle Scholar
- Karhausen J, Furuta GT, Tomaszewski JE, Johnson RS, Colgan SP, Haase VH (2004) Epithelial hypoxia-inducible factor-1 is protective in murine experimental colitis. J Clin Invest 114:1098–1106. doi:10.1172/JCI200421086 View ArticlePubMedPubMed CentralGoogle Scholar
- Tacchini L, Dansi P, Matteucci E, Desiderio MA (2001) Hepatocyte growth factor signalling stimulates hypoxia inducible factor-1 (HIF-1) activity in HepG2 hepatoma cells. Carcinogenesis 22:1363–1371. doi:10.1093/carcin/22.9.1363 View ArticlePubMedGoogle Scholar
- Gusarova GA, Trejo HE, Dada LA, Briva A, Welch LC, Hamanaka RB, Mutlu GM, Chandel NS, Prakriya M, Sznajder JI (2011) Hypoxia leads to Na, K-ATPase downregulation via Ca(2+) release-activated Ca(2+) channels and AMPK activation. Mol Cell Biol 31:3546–56. doi:10.1128/MCB.05114-11 View ArticlePubMedPubMed CentralGoogle Scholar
- Yamamoto H, Mukaisho K, Sugihara H, Hattori T, Asano S (2011) Down-regulation of FXYD3 is induced by transforming growth factor-β signaling via ZEB1/δEF1 in human mammary epithelial cells. Biol Pharm Bull 34:324–9. doi:10.1248/bpb.34.324 View ArticlePubMedGoogle Scholar
- Okudela K, Yazawa T, Ishii J, Woo T, Mitsui H, Bunai T, Sakaeda M, Shimoyamada H, Sato H, Tajiri M, Ogawa N, Masuda M, Sugimura H, Kitamura H (2009) Down-regulation of FXYD3 expression in human lung cancers: its mechanism and potential role in carcinogenesis. Am J Pathol 175:2646–2656. doi:10.2353/ajpath.2009.080571 View ArticlePubMedPubMed CentralGoogle Scholar
- Linden SK, Sutton P, Karlsson NG, Korolik V, McGuckin M a (2008) Mucins in the mucosal barrier to infection. Mucosal Immunol 1:183–197. doi:10.1038/mi.2008.5 View ArticlePubMedGoogle Scholar
- Vimal DB, Khullar M, Gupta S, Ganguly NK (2000) Intestinal mucins: the binding sites for Salmonella typhimurium. Mol Cell Biochem 204:107–117View ArticlePubMedGoogle Scholar
- Mantle M, Husar SD (1994) Binding of Yersinia enterocolitica to purified, native small intestinal mucins from rabbits and humans involves interactions with the mucin carbohydrate moiety. Infect Immun 62:1219–27PubMedPubMed CentralGoogle Scholar
- Bergstrom KSB, Kissoon-Singh V, Gibson DL, Ma C, Montero M, Sham HP, Ryz N, Huang T, Velcich A, Finlay BB, Chadee K, Vallance BA (2010) Muc2 protects against lethal infectious colitis by disassociating pathogenic and commensal bacteria from the colonic mucosa. PLoS Pathog 6:e1000902. doi:10.1371/journal.ppat.1000902 View ArticlePubMedPubMed CentralGoogle Scholar
- Aubert S, Fauquette V, Hemon B, Lepoivre R, Briez N, Bernard D, Van Seuningen I, Leroy X, Perrais M (2009) MUC1, a new hypoxia inducible factor target gene, is an actor in clear renal cell carcinoma tumor progression. Cancer Res 69:5707–5715. doi:10.1158/0008-5472.CAN-08-4905 View ArticlePubMedGoogle Scholar
- Dilly AK, Lee YJ, Zeh HJ, Guo ZS, Bartlett DL, Choudry HA (2016) Targeting hypoxia-mediated mucin 2 production as a therapeutic strategy for mucinous tumors. Transl Res 169:19–30.e1. doi:10.1016/j.trsl.2015.10.006 View ArticlePubMedGoogle Scholar
- Cummins EP, Doherty G a, Taylor CT (2013) Hydroxylases as therapeutic targets in inflammatory bowel disease. Lab Investig 93:378–383. doi:10.1038/labinvest.2013.9 View ArticlePubMedGoogle Scholar
- Giatromanolaki A, Sivridis E, Maltezos E, Papazoglou D, Simopoulos C, Gatter KC, Harris a L, Koukourakis MI (2003) Hypoxia inducible factor 1alpha and 2alpha overexpression in inflammatory bowel disease. J Clin Pathol 56:209–213View ArticlePubMedPubMed CentralGoogle Scholar
- Cummins EP, Seeballuck F, Keely SJ, Mangan NE, Callanan JJ, Fallon PG, Taylor CT (2008) The hydroxylase inhibitor dimethyloxalylglycine is protective in a murine model of colitis. Gastroenterology 134:156–165. doi:10.1053/j.gastro.2007.10.012 View ArticlePubMedGoogle Scholar
- Hirota S a, Fines K, Ng J, Traboulsi D, Lee J, Ihara E, Li Y, Willmore WG, Chung D, Scully MM, Louie T, Medlicott S, Lejeune M, Chadee K, Armstrong G, Colgan SP, Muruve D a, MacDonald J a, Beck PL (2010) Hypoxia-inducible factor signaling provides protection in clostridium difficile-induced intestinal injury. Gastroenterology 139:259–269.e3. doi:10.1053/j.gastro.2010.03.045 View ArticlePubMedPubMed CentralGoogle Scholar
- Bhandari T, Nizet V (2014) Hypoxia-inducible factor (HIF) as a pharmacological target for prevention and treatment of infectious diseases. Infect Dis Ther 159–174. doi: 10.1007/s40121-014-0030-1Google Scholar
- Zinkernagel AS, Johnson RS, Nizet V (2007) Hypoxia inducible factor (HIF) function in innate immunity and infection. J Mol Med 85:1339–1346. doi:10.1007/s00109-007-0282-2 View ArticlePubMedGoogle Scholar
- Zinkernagel AS, Peyssonnaux C, Johnson RS, Nizet V (2008) Pharmacologic augmentation of hypoxia-inducible factor-1alpha with mimosine boosts the bactericidal capacity of phagocytes. J Infect Dis 197:214–217. doi:10.1086/524843 View ArticlePubMedGoogle Scholar
- Robinson A, Keely S, Karhausen J, Gerich ME, Furuta GT, Colgan SP (2008) Mucosal protection by hypoxia-inducible factor prolyl hydroxylase inhibition. Gastroenterology 134:145–155. doi:10.1053/j.gastro.2007.09.033 View ArticlePubMedPubMed CentralGoogle Scholar
- Tran Van Nhieu G, Bourdet-Sicard R, Dumenil G, Blocker A, Sansonetti PJ (2000) Bacterial signals and cell responses using Shigella entry into epithelial cells. Cell Microbiol 2:187–193. doi:10.1046/j.1462-5822.2000.00046.x View ArticlePubMedGoogle Scholar