PMCCPMCCPMCC

Search tips
Search criteria 

Advanced

 
Logo of jcinvestThe Journal of Clinical Investigation
 
J Clin Invest. 1995 January; 95(1): 55–65.
PMCID: PMC295369

A distinct array of proinflammatory cytokines is expressed in human colon epithelial cells in response to bacterial invasion.

Abstract

Pathogenic bacteria that penetrate the intestinal epithelial barrier stimulate an inflammatory response in the adjacent intestinal mucosa. The present studies asked whether colon epithelial cells can provide signals that are important for the initiation and amplification of an acute mucosal inflammatory response. Infection of monolayers of human colon epithelial cell lines (T84, HT29, Caco-2) with invasive strains of bacteria (Salmonella dublin, Shigella dysenteriae, Yersinia enterocolitica, Listeria monocytogenes, enteroinvasive Escherichia coli) resulted in the coordinate expression and upregulation of a specific array of four proinflammatory cytokines, IL-8, monocyte chemotactic protein-1, GM-CSF, and TNF alpha, as assessed by mRNA levels and cytokine secretion. Expression of the same cytokines was upregulated after TNF alpha or IL-1 stimulation of these cells. In contrast, cytokine gene expression was not altered after infection of colon epithelial cells with noninvasive bacteria or the noninvasive protozoan parasite, G. lamblia. Notably, none of the cell lines expressed mRNA for IL-2, IL-4, IL-5, IL-6, IL-12p40, IFN-gamma, or significant levels of IL-1 or IL-10 in response to the identical stimuli. The coordinate expression of IL-8, MCP-1, GM-CSF and TNF alpha appears to be a general property of human colon epithelial cells since an identical array of cytokines, as well as IL-6, also was expressed by freshly isolated human colon epithelial cells. Since the cytokines expressed in response to bacterial invasion or other proinflammatory agonists have a well documented role in chemotaxis and activation of inflammatory cells, colon epithelial cells appear to be programmed to provide a set of signals for the activation of the mucosal inflammatory response in the earliest phases after microbial invasion.

Full text

Full text is available as a scanned copy of the original print version. Get a printable copy (PDF file) of the complete article (2.2M), or click on a page image below to browse page by page. Links to PubMed are also available for Selected References.

Images in this article

Click on the image to see a larger version.

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Mayer L, Shlien R. Evidence for function of Ia molecules on gut epithelial cells in man. J Exp Med. 1987 Nov 1;166(5):1471–1483. [PMC free article] [PubMed]
  • Selby WS, Janossy G, Mason DY, Jewell DP. Expression of HLA-DR antigens by colonic epithelium in inflammatory bowel disease. Clin Exp Immunol. 1983 Sep;53(3):614–618. [PubMed]
  • Mayer L, Eisenhardt D, Salomon P, Bauer W, Plous R, Piccinini L. Expression of class II molecules on intestinal epithelial cells in humans. Differences between normal and inflammatory bowel disease. Gastroenterology. 1991 Jan;100(1):3–12. [PubMed]
  • Kaiserlian D, Rigal D, Abello J, Revillard JP. Expression, function and regulation of the intercellular adhesion molecule-1 (ICAM-1) on human intestinal epithelial cell lines. Eur J Immunol. 1991 Oct;21(10):2415–2421. [PubMed]
  • Kvale D, Krajci P, Brandtzaeg P. Expression and regulation of adhesion molecules ICAM-1 (CD54) and LFA-3 (CD58) in human intestinal epithelial cell lines. Scand J Immunol. 1992 Jun;35(6):669–676. [PubMed]
  • Kelly CP, O'Keane JC, Orellana J, Schroy PC, 3rd, Yang S, LaMont JT, Brady HR. Human colon cancer cells express ICAM-1 in vivo and support LFA-1-dependent lymphocyte adhesion in vitro. Am J Physiol. 1992 Dec;263(6 Pt 1):G864–G870. [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]
  • 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]
  • Shirota K, LeDuy L, Yuan SY, Jothy S. Interleukin-6 and its receptor are expressed in human intestinal epithelial cells. Virchows Arch B Cell Pathol Incl Mol Pathol. 1990;58(4):303–308. [PubMed]
  • Anzano MA, Rieman D, Prichett W, Bowen-Pope DF, Greig R. Growth factor production by human colon carcinoma cell lines. Cancer Res. 1989 Jun 1;49(11):2898–2904. [PubMed]
  • Andoh A, Fujiyama Y, Bamba T, Hosoda S. Differential cytokine regulation of complement C3, C4, and factor B synthesis in human intestinal epithelial cell line, Caco-2. J Immunol. 1993 Oct 15;151(8):4239–4247. [PubMed]
  • Dias VC, Wallace JL, Parsons HG. Modulation of cellular phospholipid fatty acids and leukotriene B4 synthesis in the human intestinal cell (CaCo-2). Gut. 1992 May;33(5):622–627. [PMC free article] [PubMed]
  • Phillips JO, Everson MP, Moldoveanu Z, Lue C, Mestecky J. Synergistic effect of IL-4 and IFN-gamma on the expression of polymeric Ig receptor (secretory component) and IgA binding by human epithelial cells. J Immunol. 1990 Sep 15;145(6):1740–1744. [PubMed]
  • Mulder KM, Zhong Q, Choi HG, Humphrey LE, Brattain MG. Inhibitory effects of transforming growth factor beta 1 on mitogenic response, transforming growth factor alpha, and c-myc in quiescent, well-differentiated colon carcinoma cells. Cancer Res. 1990 Dec 1;50(23):7581–7586. [PubMed]
  • Fantini J, Bolmont C, Yahi N. Tumor necrosis factor-alpha stimulates both apical and basal production of HIV in polarized human intestinal HT29 cells. Immunol Lett. 1992 Sep;34(1):85–90. [PubMed]
  • Ullmann CD, Schlom J, Greiner JW. Interleukin-6 increases carcinoembryonic antigen and histocompatibility leukocyte antigen expression on the surface of human colorectal carcinoma cells. J Immunother (1991) 1992 Nov;12(4):231–241. [PubMed]
  • Das KM, Squillante L, Robertson FM. Amplified expression of intercellular adhesion molecule-1 (ICAM-1) and M(r) 40K protein by DLD-1 colon tumor cells by interferon-gamma. Cell Immunol. 1993 Mar;147(1):215–221. [PubMed]
  • Raitano AB, Korc M. Growth inhibition of a human colorectal carcinoma cell line by interleukin 1 is associated with enhanced expression of gamma-interferon receptors. Cancer Res. 1993 Feb 1;53(3):636–640. [PubMed]
  • Mosmann TR, Coffman RL. TH1 and TH2 cells: different patterns of lymphokine secretion lead to different functional properties. Annu Rev Immunol. 1989;7:145–173. [PubMed]
  • Wierenga EA, Snoek M, Jansen HM, Bos JD, van Lier RA, Kapsenberg ML. Human atopen-specific types 1 and 2 T helper cell clones. J Immunol. 1991 Nov 1;147(9):2942–2949. [PubMed]
  • Del Prete GF, De Carli M, Mastromauro C, Biagiotti R, Macchia D, Falagiani P, Ricci M, Romagnani S. Purified protein derivative of Mycobacterium tuberculosis and excretory-secretory antigen(s) of Toxocara canis expand in vitro human T cells with stable and opposite (type 1 T helper or type 2 T helper) profile of cytokine production. J Clin Invest. 1991 Jul;88(1):346–350. [PMC free article] [PubMed]
  • Mahanty S, King CL, Kumaraswami V, Regunathan J, Maya A, Jayaraman K, Abrams JS, Ottesen EA, Nutman TB. IL-4- and IL-5-secreting lymphocyte populations are preferentially stimulated by parasite-derived antigens in human tissue invasive nematode infections. J Immunol. 1993 Oct 1;151(7):3704–3711. [PubMed]
  • Yamamura M, Uyemura K, Deans RJ, Weinberg K, Rea TH, Bloom BR, Modlin RL. Defining protective responses to pathogens: cytokine profiles in leprosy lesions. Science. 1991 Oct 11;254(5029):277–279. [PubMed]
  • Yamamura M, Wang XH, Ohmen JD, Uyemura K, Rea TH, Bloom BR, Modlin RL. Cytokine patterns of immunologically mediated tissue damage. J Immunol. 1992 Aug 15;149(4):1470–1475. [PubMed]
  • Pirmez C, Yamamura M, Uyemura K, Paes-Oliveira M, Conceiço-Silva F, Modlin RL. Cytokine patterns in the pathogenesis of human leishmaniasis. J Clin Invest. 1993 Apr;91(4):1390–1395. [PMC free article] [PubMed]
  • Shull MM, Ormsby I, Kier AB, Pawlowski S, Diebold RJ, Yin M, Allen R, Sidman C, Proetzel G, Calvin D, et al. Targeted disruption of the mouse transforming growth factor-beta 1 gene results in multifocal inflammatory disease. Nature. 1992 Oct 22;359(6397):693–699. [PubMed]
  • Wahl SM. Transforming growth factor beta (TGF-beta) in inflammation: a cause and a cure. J Clin Immunol. 1992 Mar;12(2):61–74. [PubMed]
  • Cassatella MA, Meda L, Bonora S, Ceska M, Constantin G. Interleukin 10 (IL-10) inhibits the release of proinflammatory cytokines from human polymorphonuclear leukocytes. Evidence for an autocrine role of tumor necrosis factor and IL-1 beta in mediating the production of IL-8 triggered by lipopolysaccharide. J Exp Med. 1993 Dec 1;178(6):2207–2211. [PMC free article] [PubMed]
  • Standiford TJ, Kunkel SL, Basha MA, Chensue SW, Lynch JP, 3rd, Toews GB, Westwick J, Strieter RM. Interleukin-8 gene expression by a pulmonary epithelial cell line. A model for cytokine networks in the lung. J Clin Invest. 1990 Dec;86(6):1945–1953. [PMC free article] [PubMed]
  • Wang AM, Doyle MV, Mark DF. Quantitation of mRNA by the polymerase chain reaction. Proc Natl Acad Sci U S A. 1989 Dec;86(24):9717–9721. [PubMed]
  • Chikami GK, Fierer J, Guiney DG. Plasmid-mediated virulence in Salmonella dublin demonstrated by use of a Tn5-oriT construct. Infect Immun. 1985 Nov;50(2):420–424. [PMC free article] [PubMed]
  • Gillin FD, Reiner DS, Boucher SE. Small-intestinal factors promote encystation of Giardia lamblia in vitro. Infect Immun. 1988 Mar;56(3):705–707. [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]
  • Kekow J, Wachsman W, McCutchan JA, Gross WL, Zachariah M, Carson DA, Lotz M. Transforming growth factor-beta and suppression of humoral immune responses in HIV infection. J Clin Invest. 1991 Mar;87(3):1010–1016. [PMC free article] [PubMed]
  • Ciacci C, Mahida YR, Dignass A, Koizumi M, Podolsky DK. Functional interleukin-2 receptors on intestinal epithelial cells. J Clin Invest. 1993 Jul;92(1):527–532. [PMC free article] [PubMed]
  • Oppenheim JJ, Zachariae CO, Mukaida N, Matsushima K. Properties of the novel proinflammatory supergene "intercrine" cytokine family. Annu Rev Immunol. 1991;9:617–648. [PubMed]
  • Danis VA, Franic GM, Rathjen DA, Brooks PM. Effects of granulocyte-macrophage colony-stimulating factor (GM-CSF), IL-2, interferon-gamma (IFN-gamma), tumour necrosis factor-alpha (TNF-alpha) and IL-6 on the production of immunoreactive IL-1 and TNF-alpha by human monocytes. Clin Exp Immunol. 1991 Jul;85(1):143–150. [PubMed]
  • DeNichilo MO, Stewart AG, Vadas MA, Lopez AF. Granulocyte-macrophage colony-stimulating factor is a stimulant of platelet-activating factor and superoxide anion generation by human neutrophils. J Biol Chem. 1991 Mar 15;266(8):4896–4902. [PubMed]
  • Ferrante A. Activation of neutrophils by interleukins-1 and -2 and tumor necrosis factors. Immunol Ser. 1992;57:417–436. [PubMed]
  • Lopez AF, Elliott MJ, Woodcock J, Vadas MA. GM-CSF, IL-3 and IL-5: cross-competition on human haemopoietic cells. Immunol Today. 1992 Dec;13(12):495–500. [PubMed]
  • Dinarello CA. Interleukin-1 and interleukin-1 antagonism. Blood. 1991 Apr 15;77(8):1627–1652. [PubMed]
  • D'Andrea A, Rengaraju M, Valiante NM, Chehimi J, Kubin M, Aste M, Chan SH, Kobayashi M, Young D, Nickbarg E, et al. Production of natural killer cell stimulatory factor (interleukin 12) by peripheral blood mononuclear cells. J Exp Med. 1992 Nov 1;176(5):1387–1398. [PMC free article] [PubMed]
  • Trinchieri G. Interleukin-12 and its role in the generation of TH1 cells. Immunol Today. 1993 Jul;14(7):335–338. [PubMed]
  • Youngman KR, Simon PL, West GA, Cominelli F, Rachmilewitz D, Klein JS, Fiocchi C. Localization of intestinal interleukin 1 activity and protein and gene expression to lamina propria cells. Gastroenterology. 1993 Mar;104(3):749–758. [PubMed]
  • Lorenzen J, Lewis CE, McCracken D, Horak E, Greenall M, McGee JO. Human tumour-associated NK cells secrete increased amounts of interferon-gamma and interleukin-4. Br J Cancer. 1991 Sep;64(3):457–462. [PMC free article] [PubMed]
  • Bradding P, Feather IH, Wilson S, Bardin PG, Heusser CH, Holgate ST, Howarth PH. Immunolocalization of cytokines in the nasal mucosa of normal and perennial rhinitic subjects. The mast cell as a source of IL-4, IL-5, and IL-6 in human allergic mucosal inflammation. J Immunol. 1993 Oct 1;151(7):3853–3865. [PubMed]
  • Galli SJ, Gordon JR, Wershil BK. Mast cell cytokines in allergy and inflammation. Agents Actions Suppl. 1993;43:209–220. [PubMed]
  • Desreumaux P, Janin A, Colombel JF, Prin L, Plumas J, Emilie D, Torpier G, Capron A, Capron M. Interleukin 5 messenger RNA expression by eosinophils in the intestinal mucosa of patients with coeliac disease. J Exp Med. 1992 Jan 1;175(1):293–296. [PMC free article] [PubMed]
  • Hedges S, Svensson M, Svanborg C. Interleukin-6 response of epithelial cell lines to bacterial stimulation in vitro. Infect Immun. 1992 Apr;60(4):1295–1301. [PMC free article] [PubMed]
  • Karakurum M, Shreeniwas R, Chen J, Pinsky D, Yan SD, Anderson M, Sunouchi K, Major J, Hamilton T, Kuwabara K, et al. Hypoxic induction of interleukin-8 gene expression in human endothelial cells. J Clin Invest. 1994 Apr;93(4):1564–1570. [PMC free article] [PubMed]
  • Kühn R, Löhler J, Rennick D, Rajewsky K, Müller W. Interleukin-10-deficient mice develop chronic enterocolitis. Cell. 1993 Oct 22;75(2):263–274. [PubMed]

Articles from The Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation