Search tips
Search criteria 


Logo of jcellbiolHomeThe Rockefeller University PressEditorsContactInstructions for AuthorsThis issue
J Cell Biol. 1995 December 2; 131(6): 1599–1608.
PMCID: PMC2120679

Surface attachment of Salmonella typhimurium to intestinal epithelia imprints the subepithelial matrix with gradients chemotactic for neutrophils


During intestinal disease induced by Salmonella typhimurium transepithelial migration of neutrophils (PMN) rapidly follows attachment of the bacteria to the epithelial apical membrane. Among the events stimulated by these interactions is the release of chemotaxins that guide PMN through the subepithelial matrix and subsequently through the epithelium itself (McCormick, B.A., S.P. Colgan, C. Delp- Archer, S.I. Miller, and J.L. Madara. 1993. J. Cell Biol. 123:895-907). Given the substantial volume flow that normally characterizes matrix compartments underlying transporting epithelia, it is unclear how such transmatrix signaling is sustained. Here we show that when underlying matrices are isolated from biophysically confluent polarized monolayers of the human intestinal epithelial cell line T84, they fail to support substantial transmatrix migration of PMN unless an exogenous chemotactic gradient is imposed. In contrast, such matrices isolated from confluent monolayers apically colonized with S. typhimurium support spontaneous transmatrix migration of PMN. Such chemotactic imprinting of underlying matrices is resistant to volume wash and is paralleled by secretion of the known matrix-binding chemokine IL-8. Chemotactic imprinting of the matrix underlying S. typhimurium- colonized monolayers is dependent on epithelial protein synthesis, is directional implying the existence of a gradient, and is neutralized by antibodies either to IL-8 or to the IL-8 receptor on PMN. An avirulent S. typhimurium strain, PhoPc, which attaches to epithelial cells as efficiently as wild-type S. typhimurium, fails to induce basolateral secretion of IL-8 and likewise fails to imprint matrices. Together, these observations show that the epithelial surface can respond to the presence of a luminal pathogen and subsequently imprint the subepithelial matrix with retained IL-8 gradients sufficient to resist washout effects of the volume flow that normally traverses this compartment. Such data further support the notion that the primary role for basolateral secretion of IL-8 by the intestinal and likely other epithelia is recruitment of PMN through the matrix to the subepithelial space, rather than directing the final movement of PMN across the epithelium.

Full Text

The Full Text of this article is available as a PDF (1.1M).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Agace W, Hedges S, Andersson U, Andersson J, Ceska M, Svanborg C. Selective cytokine production by epithelial cells following exposure to Escherichia coli. Infect Immun. 1993 Feb;61(2):602–609. [PMC free article] [PubMed]
  • Alpuche Aranda CM, Swanson JA, Loomis WP, Miller SI. Salmonella typhimurium activates virulence gene transcription within acidified macrophage phagosomes. Proc Natl Acad Sci U S A. 1992 Nov 1;89(21):10079–10083. [PubMed]
  • Arnaout MA. Leukocyte adhesion molecules deficiency: its structural basis, pathophysiology and implications for modulating the inflammatory response. Immunol Rev. 1990 Apr;114:145–180. [PubMed]
  • Behlau I, Miller SI. A PhoP-repressed gene promotes Salmonella typhimurium invasion of epithelial cells. J Bacteriol. 1993 Jul;175(14):4475–4484. [PMC free article] [PubMed]
  • Butcher EC. Leukocyte-endothelial cell recognition: three (or more) steps to specificity and diversity. Cell. 1991 Dec 20;67(6):1033–1036. [PubMed]
  • Chuntharapai A, Lee J, Burnier J, Wood WI, Hébert C, Kim KJ. Neutralizing monoclonal antibodies to human IL-8 receptor A map to the NH2-terminal region of the receptor. J Immunol. 1994 Feb 15;152(4):1783–1789. [PubMed]
  • Colditz I, Zwahlen R, Dewald B, Baggiolini M. In vivo inflammatory activity of neutrophil-activating factor, a novel chemotactic peptide derived from human monocytes. Am J Pathol. 1989 Apr;134(4):755–760. [PubMed]
  • Dana N, Todd RF, 3rd, Pitt J, Springer TA, Arnaout MA. Deficiency of a surface membrane glycoprotein (Mo1) in man. J Clin Invest. 1984 Jan;73(1):153–159. [PMC free article] [PubMed]
  • Day DW, Mandal BK, Morson BC. The rectal biopsy appearances in Salmonella colitis. Histopathology. 1978 Mar;2(2):117–131. [PubMed]
  • Dharmsathaphorn K, Madara JL. Established intestinal cell lines as model systems for electrolyte transport studies. Methods Enzymol. 1990;192:354–389. [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]
  • Gulig PA, Curtiss R., 3rd Plasmid-associated virulence of Salmonella typhimurium. Infect Immun. 1987 Dec;55(12):2891–2901. [PMC free article] [PubMed]
  • Hedges S, Anderson P, Lidin-Janson G, de Man P, Svanborg C. Interleukin-6 response to deliberate colonization of the human urinary tract with gram-negative bacteria. Infect Immun. 1991 Jan;59(1):421–427. [PMC free article] [PubMed]
  • Henson PM, Oades ZG. Stimulation of human neutrophils by soluble and insoluble immunoglobulin aggregates. Secretion of granule constituents and increased oxidation of glucose. J Clin Invest. 1975 Oct;56(4):1053–1061. [PMC free article] [PubMed]
  • Jodal M, Lundgren O. Countercurrent mechanisms in the mammalian gastrointestinal tract. Gastroenterology. 1986 Jul;91(1):225–241. [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]
  • Lee CA, Falkow S. The ability of Salmonella to enter mammalian cells is affected by bacterial growth state. Proc Natl Acad Sci U S A. 1990 Jun;87(11):4304–4308. [PubMed]
  • Leonard EJ, Yoshimura T, Tanaka S, Raffeld M. Neutrophil recruitment by intradermally injected neutrophil attractant/activation protein-1. J Invest Dermatol. 1991 May;96(5):690–694. [PubMed]
  • Luscinskas FW, Brock AF, Arnaout MA, Gimbrone MA., Jr Endothelial-leukocyte adhesion molecule-1-dependent and leukocyte (CD11/CD18)-dependent mechanisms contribute to polymorphonuclear leukocyte adhesion to cytokine-activated human vascular endothelium. J Immunol. 1989 Apr 1;142(7):2257–2263. [PubMed]
  • Madara JL. Warner-Lambert/Parke-Davis Award lecture. Pathobiology of the intestinal epithelial barrier. Am J Pathol. 1990 Dec;137(6):1273–1281. [PubMed]
  • Madara JL, Stafford J, Dharmsathaphorn K, Carlson S. Structural analysis of a human intestinal epithelial cell line. Gastroenterology. 1987 May;92(5 Pt 1):1133–1145. [PubMed]
  • McCormick BA, Colgan SP, Delp-Archer C, Miller SI, Madara JL. Salmonella typhimurium attachment to human intestinal epithelial monolayers: transcellular signalling to subepithelial neutrophils. J Cell Biol. 1993 Nov;123(4):895–907. [PMC free article] [PubMed]
  • McCormick BA, Miller SI, Carnes D, Madara JL. Transepithelial signaling to neutrophils by salmonellae: a novel virulence mechanism for gastroenteritis. Infect Immun. 1995 Jun;63(6):2302–2309. [PMC free article] [PubMed]
  • McElvaney NG, Nakamura H, Birrer P, Hébert CA, Wong WL, Alphonso M, Baker JB, Catalano MA, Crystal RG. Modulation of airway inflammation in cystic fibrosis. In vivo suppression of interleukin-8 levels on the respiratory epithelial surface by aerosolization of recombinant secretory leukoprotease inhibitor. J Clin Invest. 1992 Oct;90(4):1296–1301. [PMC free article] [PubMed]
  • McGovern VJ, Slavutin LJ. Pathology of salmonella colitis. Am J Surg Pathol. 1979 Dec;3(6):483–490. [PubMed]
  • McRoberts JA, Aranda R, Riley N, Kang H. Insulin regulates the paracellular permeability of cultured intestinal epithelial cell monolayers. J Clin Invest. 1990 Apr;85(4):1127–1134. [PMC free article] [PubMed]
  • Miller SI. PhoP/PhoQ: macrophage-specific modulators of Salmonella virulence? Mol Microbiol. 1991 Sep;5(9):2073–2078. [PubMed]
  • Miller SI, Mekalanos JJ. Constitutive expression of the phoP regulon attenuates Salmonella virulence and survival within macrophages. J Bacteriol. 1990 May;172(5):2485–2490. [PMC free article] [PubMed]
  • Nakamura H, Yoshimura K, McElvaney NG, Crystal RG. Neutrophil elastase in respiratory epithelial lining fluid of individuals with cystic fibrosis induces interleukin-8 gene expression in a human bronchial epithelial cell line. J Clin Invest. 1992 May;89(5):1478–1484. [PMC free article] [PubMed]
  • Nash S, Parkos C, Nusrat A, Delp C, Madara JL. In vitro model of intestinal crypt abscess. A novel neutrophil-derived secretagogue activity. J Clin Invest. 1991 Apr;87(4):1474–1477. [PMC free article] [PubMed]
  • Osborn L. Leukocyte adhesion to endothelium in inflammation. Cell. 1990 Jul 13;62(1):3–6. [PubMed]
  • Parkos CA, Delp C, Arnaout MA, Madara JL. Neutrophil migration across a cultured intestinal epithelium. Dependence on a CD11b/CD18-mediated event and enhanced efficiency in physiological direction. J Clin Invest. 1991 Nov;88(5):1605–1612. [PMC free article] [PubMed]
  • Parkos CA, Colgan SP, Delp C, Arnaout MA, Madara JL. Neutrophil migration across a cultured epithelial monolayer elicits a biphasic resistance response representing sequential effects on transcellular and paracellular pathways. J Cell Biol. 1992 May;117(4):757–764. [PMC free article] [PubMed]
  • Pegues DA, Hantman MJ, Behlau I, Miller SI. PhoP/PhoQ transcriptional repression of Salmonella typhimurium invasion genes: evidence for a role in protein secretion. Mol Microbiol. 1995 Jul;17(1):169–181. [PubMed]
  • Pober JS, Gimbrone MA, Jr, Lapierre LA, Mendrick DL, Fiers W, Rothlein R, Springer TA. Overlapping patterns of activation of human endothelial cells by interleukin 1, tumor necrosis factor, and immune interferon. J Immunol. 1986 Sep 15;137(6):1893–1896. [PubMed]
  • Revel HR. Restriction of nonglucosylated T-even bacteriophage: properties of permissive mutants of Escherichia coli B and K12. Virology. 1967 Apr;31(4):688–701. [PubMed]
  • Rout WR, Formal SB, Dammin GJ, Giannella RA. Pathophysiology of Salmonella diarrhea in the Rhesus monkey: Intestinal transport, morphological and bacteriological studies. Gastroenterology. 1974 Jul;67(1):59–70. [PubMed]
  • Schubert D, LaCorbiere M. A role of secreted glycosaminoglycans in cell-substratum adhesion. J Biol Chem. 1980 Dec 10;255(23):11564–11569. [PubMed]
  • Smith CW, Rothlein R, Hughes BJ, Mariscalco MM, Rudloff HE, Schmalstieg FC, Anderson DC. Recognition of an endothelial determinant for CD 18-dependent human neutrophil adherence and transendothelial migration. J Clin Invest. 1988 Nov;82(5):1746–1756. [PMC free article] [PubMed]
  • Swensson O, Schubert C, Christophers E, Schröder JM. Inflammatory properties of neutrophil-activating protein-1/interleukin 8 (NAP-1/IL-8) in human skin: a light- and electronmicroscopic study. J Invest Dermatol. 1991 May;96(5):682–689. [PubMed]
  • Takeuchi A. Electron microscope studies of experimental Salmonella infection. I. Penetration into the intestinal epithelium by Salmonella typhimurium. Am J Pathol. 1967 Jan;50(1):109–136. [PubMed]
  • Wang JM, Taraboletti G, Matsushima K, Van Damme J, Mantovani A. Induction of haptotactic migration of melanoma cells by neutrophil activating protein/interleukin-8. Biochem Biophys Res Commun. 1990 May 31;169(1):165–170. [PubMed]

Articles from The Journal of Cell Biology are provided here courtesy of The Rockefeller University Press