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J Clin Invest. Nov 15, 1998; 102(10): 1815–1823.
PMCID: PMC509131

Apoptosis of human intestinal epithelial cells after bacterial invasion.


Epithelial cells that line the human intestinal mucosa are the initial site of host invasion by bacterial pathogens. The studies herein define apoptosis as a new category of intestinal epithelial cell response to bacterial infection. Human colon epithelial cells are shown to undergo apoptosis following infection with invasive enteric pathogens, such as Salmonella or enteroinvasive Escherichia coli. In contrast to the rapid onset of apoptosis seen after bacterial infection of mouse monocyte-macrophage cell lines, the commitment of human intestinal epithelial cell lines to undergo apoptosis is delayed for at least 6 h after bacterial infection, requires bacterial entry and replication, and the ensuing phenotypic expression of apoptosis is delayed for 12-18 h after bacterial entry. TNF-alpha and nitric oxide, which are produced as components of the intestinal epithelial cell proinflammatory program in the early period after bacterial invasion, play an important role in the later induction and regulation of the epithelial cell apoptotic program. Apoptosis in response to bacterial infection may function to delete infected and damaged epithelial cells and restore epithelial cell growth regulation and epithelial integrity that are altered during the course of enteric infection. The delay in onset of epithelial cell apoptosis after bacterial infection may be important both to the host and the invading pathogen since it provides sufficient time for epithelial cells to generate signals important for the activation of mucosal inflammation and concurrently allows invading bacteria time to adapt to the intracellular environment before invading deeper mucosal layers.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Wright NA, Irwin M. The kinetics of villus cell populations in the mouse small intestine. I. Normal villi: the steady state requirement. Cell Tissue Kinet. 1982 Nov;15(6):595–609. [PubMed]
  • Hockenbery D. Defining apoptosis. Am J Pathol. 1995 Jan;146(1):16–19. [PMC free article] [PubMed]
  • Hall PA, Coates PJ, Ansari B, Hopwood D. Regulation of cell number in the mammalian gastrointestinal tract: the importance of apoptosis. J Cell Sci. 1994 Dec;107(Pt 12):3569–3577. [PubMed]
  • Potten CS. The significance of spontaneous and induced apoptosis in the gastrointestinal tract of mice. Cancer Metastasis Rev. 1992 Sep;11(2):179–195. [PubMed]
  • Iwanaga T, Han H, Adachi K, Fujita T. A novel mechanism for disposing of effete epithelial cells in the small intestine of guinea pigs. Gastroenterology. 1993 Oct;105(4):1089–1097. [PubMed]
  • Abreu-Martin MT, Vidrich A, Lynch DH, Targan SR. Divergent induction of apoptosis and IL-8 secretion in HT-29 cells in response to TNF-alpha and ligation of Fas antigen. J Immunol. 1995 Nov 1;155(9):4147–4154. [PubMed]
  • Browning JL, Miatkowski K, Sizing I, Griffiths D, Zafari M, Benjamin CD, Meier W, Mackay F. Signaling through the lymphotoxin beta receptor induces the death of some adenocarcinoma tumor lines. J Exp Med. 1996 Mar 1;183(3):867–878. [PMC free article] [PubMed]
  • Yonehara S, Ishii A, Yonehara M. A cell-killing monoclonal antibody (anti-Fas) to a cell surface antigen co-downregulated with the receptor of tumor necrosis factor. J Exp Med. 1989 May 1;169(5):1747–1756. [PMC free article] [PubMed]
  • Clayton F, Reka S, Cronin WJ, Torlakovic E, Sigal SH, Kotler DP. Rectal mucosal pathology varies with human immunodeficiency virus antigen content and disease stage. Gastroenterology. 1992 Sep;103(3):919–933. [PubMed]
  • Islam D, Veress B, Bardhan PK, Lindberg AA, Christensson B. In situ characterization of inflammatory responses in the rectal mucosae of patients with shigellosis. Infect Immun. 1997 Feb;65(2):739–749. [PMC free article] [PubMed]
  • Eckmann L, Kagnoff MF, Fierer J. Epithelial cells secrete the chemokine interleukin-8 in response to bacterial entry. Infect Immun. 1993 Nov;61(11):4569–4574. [PMC free article] [PubMed]
  • Jung HC, Eckmann L, Yang SK, Panja A, Fierer J, Morzycka-Wroblewska E, Kagnoff MF. A distinct array of proinflammatory cytokines is expressed in human colon epithelial cells in response to bacterial invasion. J Clin Invest. 1995 Jan;95(1):55–65. [PMC free article] [PubMed]
  • Yang SK, Eckmann L, Panja A, Kagnoff MF. Differential and regulated expression of C-X-C, C-C, and C-chemokines by human colon epithelial cells. Gastroenterology. 1997 Oct;113(4):1214–1223. [PubMed]
  • Witthöft T, Eckmann L, Kim JM, Kagnoff MF. Enteroinvasive bacteria directly activate expression of iNOS and NO production in human colon epithelial cells. Am J Physiol. 1998 Sep;275(3 Pt 1):G564–G571. [PubMed]
  • Kagnoff MF, Eckmann L. Epithelial cells as sensors for microbial infection. J Clin Invest. 1997 Jul 1;100(1):6–10. [PMC free article] [PubMed]
  • Zychlinsky A, Prevost MC, Sansonetti PJ. Shigella flexneri induces apoptosis in infected macrophages. Nature. 1992 Jul 9;358(6382):167–169. [PubMed]
  • Monack DM, Raupach B, Hromockyj AE, Falkow S. Salmonella typhimurium invasion induces apoptosis in infected macrophages. Proc Natl Acad Sci U S A. 1996 Sep 3;93(18):9833–9838. [PMC free article] [PubMed]
  • Mills SD, Boland A, Sory MP, van der Smissen P, Kerbourch C, Finlay BB, Cornelis GR. Yersinia enterocolitica induces apoptosis in macrophages by a process requiring functional type III secretion and translocation mechanisms and involving YopP, presumably acting as an effector protein. Proc Natl Acad Sci U S A. 1997 Nov 11;94(23):12638–12643. [PMC free article] [PubMed]
  • Fernandez-Prada CM, Hoover DL, Tall BD, Venkatesan MM. Human monocyte-derived macrophages infected with virulent Shigella flexneri in vitro undergo a rapid cytolytic event similar to oncosis but not apoptosis. Infect Immun. 1997 Apr;65(4):1486–1496. [PMC free article] [PubMed]
  • Mantis N, Prévost MC, Sansonetti P. Analysis of epithelial cell stress response during infection by Shigella flexneri. Infect Immun. 1996 Jul;64(7):2474–2482. [PMC free article] [PubMed]
  • Eckmann L, Jung HC, Schürer-Maly C, Panja A, Morzycka-Wroblewska E, Kagnoff MF. Differential cytokine expression by human intestinal epithelial cell lines: regulated expression of interleukin 8. Gastroenterology. 1993 Dec;105(6):1689–1697. [PubMed]
  • Segall T, Lindberg AA. Oral vaccination of calves with an aromatic-dependent Salmonella dublin (O9,12) hybrid expressing O4,12 protects against S. dublin (O9,12) but not against Salmonella typhimurium (O4,5,12). Infect Immun. 1993 Apr;61(4):1222–1231. [PMC free article] [PubMed]
  • Hoiseth SK, Stocker BA. Aromatic-dependent Salmonella typhimurium are non-virulent and effective as live vaccines. Nature. 1981 May 21;291(5812):238–239. [PubMed]
  • Galán JE, Curtiss R., 3rd Distribution of the invA, -B, -C, and -D genes of Salmonella typhimurium among other Salmonella serovars: invA mutants of Salmonella typhi are deficient for entry into mammalian cells. Infect Immun. 1991 Sep;59(9):2901–2908. [PMC free article] [PubMed]
  • Eckmann L, Stenson WF, Savidge TC, Lowe DC, Barrett KE, Fierer J, Smith JR, Kagnoff MF. Role of intestinal epithelial cells in the host secretory response to infection by invasive bacteria. Bacterial entry induces epithelial prostaglandin h synthase-2 expression and prostaglandin E2 and F2alpha production. J Clin Invest. 1997 Jul 15;100(2):296–309. [PMC free article] [PubMed]
  • Duke RC, Witter RZ, Nash PB, Young JD, Ojcius DM. Cytolysis mediated by ionophores and pore-forming agents: role of intracellular calcium in apoptosis. FASEB J. 1994 Feb;8(2):237–246. [PubMed]
  • Filep JG, Baron C, Lachance S, Perreault C, Chan JS. Involvement of nitric oxide in target-cell lysis and DNA fragmentation induced by murine natural killer cells. Blood. 1996 Jun 15;87(12):5136–5143. [PubMed]
  • Zamzami N, Marchetti P, Castedo M, Zanin C, Vayssière JL, Petit PX, Kroemer G. Reduction in mitochondrial potential constitutes an early irreversible step of programmed lymphocyte death in vivo. J Exp Med. 1995 May 1;181(5):1661–1672. [PMC free article] [PubMed]
  • Kluck RM, Martin SJ, Hoffman BM, Zhou JS, Green DR, Newmeyer DD. Cytochrome c activation of CPP32-like proteolysis plays a critical role in a Xenopus cell-free apoptosis system. EMBO J. 1997 Aug 1;16(15):4639–4649. [PMC free article] [PubMed]
  • Martin SJ, Reutelingsperger CP, McGahon AJ, Rader JA, van Schie RC, LaFace DM, Green DR. Early redistribution of plasma membrane phosphatidylserine is a general feature of apoptosis regardless of the initiating stimulus: inhibition by overexpression of Bcl-2 and Abl. J Exp Med. 1995 Nov 1;182(5):1545–1556. [PMC free article] [PubMed]
  • Koopman G, Reutelingsperger CP, Kuijten GA, Keehnen RM, Pals ST, van Oers MH. Annexin V for flow cytometric detection of phosphatidylserine expression on B cells undergoing apoptosis. Blood. 1994 Sep 1;84(5):1415–1420. [PubMed]
  • Cormack BP, Valdivia RH, Falkow S. FACS-optimized mutants of the green fluorescent protein (GFP). Gene. 1996;173(1 Spec No):33–38. [PubMed]
  • Green LC, Wagner DA, Glogowski J, Skipper PL, Wishnok JS, Tannenbaum SR. Analysis of nitrate, nitrite, and [15N]nitrate in biological fluids. Anal Biochem. 1982 Oct;126(1):131–138. [PubMed]
  • Huang GT, Eckmann L, Savidge TC, Kagnoff MF. Infection of human intestinal epithelial cells with invasive bacteria upregulates apical intercellular adhesion molecule-1 (ICAM)-1) expression and neutrophil adhesion. J Clin Invest. 1996 Jul 15;98(2):572–583. [PMC free article] [PubMed]
  • Van Antwerp DJ, Martin SJ, Kafri T, Green DR, Verma IM. Suppression of TNF-alpha-induced apoptosis by NF-kappaB. Science. 1996 Nov 1;274(5288):787–789. [PubMed]
  • Grell M, Zimmermann G, Hülser D, Pfizenmaier K, Scheurich P. TNF receptors TR60 and TR80 can mediate apoptosis via induction of distinct signal pathways. J Immunol. 1994 Sep 1;153(5):1963–1972. [PubMed]
  • Ruggiero V, Tavernier J, Fiers W, Baglioni C. Induction of the synthesis of tumor necrosis factor receptors by interferon-gamma. J Immunol. 1986 Apr 1;136(7):2445–2450. [PubMed]
  • Sandoval M, Zhang XJ, Liu X, Mannick EE, Clark DA, Miller MJ. Peroxynitrite-induced apoptosis in T84 and RAW 264.7 cells: attenuation by L-ascorbic acid. Free Radic Biol Med. 1997;22(3):489–495. [PubMed]
  • Enari M, Sakahira H, Yokoyama H, Okawa K, Iwamatsu A, Nagata S. A caspase-activated DNase that degrades DNA during apoptosis, and its inhibitor ICAD. Nature. 1998 Jan 1;391(6662):43–50. [PubMed]
  • Zychlinsky A, Sansonetti P. Perspectives series: host/pathogen interactions. Apoptosis in bacterial pathogenesis. J Clin Invest. 1997 Aug 1;100(3):493–495. [PMC free article] [PubMed]
  • Thirumalai K, Kim KS, Zychlinsky A. IpaB, a Shigella flexneri invasin, colocalizes with interleukin-1 beta-converting enzyme in the cytoplasm of macrophages. Infect Immun. 1997 Feb;65(2):787–793. [PMC free article] [PubMed]
  • Dyer RB, Collaco CR, Niesel DW, Herzog NK. Shigella flexneri invasion of HeLa cells induces NF-kappa B DNA-binding activity. Infect Immun. 1993 Oct;61(10):4427–4433. [PMC free article] [PubMed]
  • Beg AA, Baltimore D. An essential role for NF-kappaB in preventing TNF-alpha-induced cell death. Science. 1996 Nov 1;274(5288):782–784. [PubMed]
  • Clifton DR, Goss RA, Sahni SK, van Antwerp D, Baggs RB, Marder VJ, Silverman DJ, Sporn LA. NF-kappa B-dependent inhibition of apoptosis is essential for host cellsurvival during Rickettsia rickettsii infection. Proc Natl Acad Sci U S A. 1998 Apr 14;95(8):4646–4651. [PMC free article] [PubMed]
  • Finlay BB, Cossart P. Exploitation of mammalian host cell functions by bacterial pathogens. Science. 1997 May 2;276(5313):718–725. [PubMed]
  • Savidge TC, Morey AL, Ferguson DJ, Fleming KA, Shmakov AN, Phillips AD. Human intestinal development in a severe-combined immunodeficient xenograft model. Differentiation. 1995 Jun;58(5):361–371. [PubMed]
  • Mathan MM, Mathan VI. Morphology of rectal mucosa of patients with shigellosis. Rev Infect Dis. 1991 Mar-Apr;13 (Suppl 4):S314–S318. [PubMed]
  • Savidge TC, Shmakov AN, Walker-Smith JA, Phillips AD. Epithelial cell proliferation in childhood enteropathies. Gut. 1996 Aug;39(2):185–193. [PMC free article] [PubMed]
  • Islam MM, Azad AK, Bardhan PK, Raqib R, Islam D. Pathology of shigellosis and its complications. Histopathology. 1994 Jan;24(1):65–71. [PubMed]
  • Sachdev HP, Chadha V, Malhotra V, Verghese A, Puri RK. Rectal histopathology in endemic Shigella and Salmonella diarrhea. J Pediatr Gastroenterol Nutr. 1993 Jan;16(1):33–38. [PubMed]
  • Tsujii M, DuBois RN. Alterations in cellular adhesion and apoptosis in epithelial cells overexpressing prostaglandin endoperoxide synthase 2. Cell. 1995 Nov 3;83(3):493–501. [PubMed]

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