Abstract
Shigella infection is accompanied by an intestinal activation of epithelial cells, T cells, and macrophages within the inflamed colonic mucosa. A prospective study was carried out to elucidate the cytokine pattern in Shigella infection linked to development of immunity and eradication of bacteria from the local site and also to correlate the cytokine profile with histological severity. An indirect immunohistochemical technique was used to determine the production and localization of various cytokines at the single-cell level in cryopreserved rectal biopsies from 24 patients with either Shigella dysenteriae type 1 (n = 18) or Shigella flexneri (n = 6) infection. The histopathological profile included presence of chronic inflammatory cells with or without neutrophils and microulcers in the lamina propria, crypt distortion, branching, and less frequently crypt abscesses. Patients had significantly higher (P < 0.005) numbers of cytokine producing cells for all of the cytokines studied, interleukin-1 alpha (IL-1 alpha), IL-1 beta, IL-1ra, tumor necrosis factor alpha (TNF-alpha), IL-6, IL-8, IL-4, IL-10, gamma interferon, TNF-beta, and transforming growth factor beta 1-3, in the biopsies than the healthy controls (n = 13). The cytokine production profile during the study period was dominated by IL-1 beta, transforming growth factor beta 1-3, IL-4, and IL-10. Significantly increased frequencies of cytokine-producing cells (P < 0.05) were observed for IL-1, IL-6, gamma interferon, and TNF-alpha in biopsies with severe inflammation in comparison with those with mild inflammation. During the acute stage of the disease, 20 of 24 patients exhibited acute inflammation in the rectal biopsies and the cellular infiltration was still extensive 30 days after the onset of diarrhea, although the disease was clinically resolved. In accordance with the histological findings, cytokine production was also upregulated during the convalescent phase; there was no significant difference (P > 0.05) in the incidence of cytokine-producing cells between acute (2 to 8 days after the onset of diarrhea) and convalescent (30 days after onset) stages.
Full Text
The Full Text of this article is available as a PDF (6.6 MB).
Selected References
These references are in PubMed. This may not be the complete list of references from this article.
- Abrams J. S., Roncarolo M. G., Yssel H., Andersson U., Gleich G. J., Silver J. E. Strategies of anti-cytokine monoclonal antibody development: immunoassay of IL-10 and IL-5 in clinical samples. Immunol Rev. 1992 Jun;127:5–24. doi: 10.1111/j.1600-065x.1992.tb01406.x. [DOI] [PubMed] [Google Scholar]
- 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. doi: 10.1128/iai.61.2.602-609.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Anand B. S., Malhotra V., Bhattacharya S. K., Datta P., Datta D., Sen D., Bhattacharya M. K., Mukherjee P. P., Pal S. C. Rectal histology in acute bacillary dysentery. Gastroenterology. 1986 Mar;90(3):654–660. doi: 10.1016/0016-5085(86)91120-0. [DOI] [PubMed] [Google Scholar]
- Andersson G., Ekre H. P., Alm G., Perlmann P. Monoclonal antibody two-site ELISA for human IFN-gamma. Adaptation for determinations in human serum or plasma. J Immunol Methods. 1989 Dec 20;125(1-2):89–96. doi: 10.1016/0022-1759(89)90081-1. [DOI] [PubMed] [Google Scholar]
- Andersson J., Abrams J., Björk L., Funa K., Litton M., Agren K., Andersson U. Concomitant in vivo production of 19 different cytokines in human tonsils. Immunology. 1994 Sep;83(1):16–24. [PMC free article] [PubMed] [Google Scholar]
- Andersson J., Björk L., Dinarello C. A., Towbin H., Andersson U. Lipopolysaccharide induces human interleukin-1 receptor antagonist and interleukin-1 production in the same cell. Eur J Immunol. 1992 Oct;22(10):2617–2623. doi: 10.1002/eji.1830221022. [DOI] [PubMed] [Google Scholar]
- Andersson U., Adolf G., Dohlsten M., Möller G., Sjögren H. O. Characterization of individual tumor necrosis factor alpha-and beta-producing cells after polyclonal T cell activation. J Immunol Methods. 1989 Oct 24;123(2):233–240. doi: 10.1016/0022-1759(89)90227-5. [DOI] [PubMed] [Google Scholar]
- Barral-Netto M., Barral A., Brownell C. E., Skeiky Y. A., Ellingsworth L. R., Twardzik D. R., Reed S. G. Transforming growth factor-beta in leishmanial infection: a parasite escape mechanism. Science. 1992 Jul 24;257(5069):545–548. doi: 10.1126/science.1636092. [DOI] [PubMed] [Google Scholar]
- Brynskov J., Tvede N., Andersen C. B., Vilien M. Increased concentrations of interleukin 1 beta, interleukin-2, and soluble interleukin-2 receptors in endoscopical mucosal biopsy specimens with active inflammatory bowel disease. Gut. 1992 Jan;33(1):55–58. doi: 10.1136/gut.33.1.55. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Butler T., Dunn D., Dahms B., Islam M. Causes of death and the histopathologic findings in fatal shigellosis. Pediatr Infect Dis J. 1989 Nov;8(11):767–772. doi: 10.1097/00006454-198911000-00008. [DOI] [PubMed] [Google Scholar]
- Degré M., Bukholm G., Czarniecki C. W. In vitro treatment of HEp-2 cells with human tumor necrosis factor-alpha and human interferons reduces invasiveness of Salmonella typhimurium. J Biol Regul Homeost Agents. 1989 Jan-Mar;3(1):1–7. [PubMed] [Google Scholar]
- Dinarello C. A., Mier J. W. Lymphokines. N Engl J Med. 1987 Oct 8;317(15):940–945. doi: 10.1056/NEJM198710083171506. [DOI] [PubMed] [Google Scholar]
- Dolhain R. J., Andersson U., ter Haar N. T., Brinkman B. M., Verweij C. L., Daha M. R., Breedveld F. C., Miltenburg A. M. Detection of intracellular interferon-gamma by light microscopy using an immunoperoxidase technique: correlation with the corresponding mRNA and protein product. J Leukoc Biol. 1993 Dec;54(6):545–551. doi: 10.1002/jlb.54.6.545. [DOI] [PubMed] [Google Scholar]
- Fontaine A., Arondel J., Sansonetti P. J. Role of Shiga toxin in the pathogenesis of bacillary dysentery, studied by using a Tox- mutant of Shigella dysenteriae 1. Infect Immun. 1988 Dec;56(12):3099–3109. doi: 10.1128/iai.56.12.3099-3109.1988. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Henry F. J., Alam N., Aziz K. M., Rahaman M. M. Dysentery, not watery diarrhoea, is associated with stunting in Bangladeshi children. Hum Nutr Clin Nutr. 1987 Jul;41(4):243–249. [PubMed] [Google Scholar]
- Izzo R. S., Witkon K., Chen A. I., Hadjiyane C., Weinstein M. I., Pellecchia C. Interleukin-8 and neutrophil markers in colonic mucosa from patients with ulcerative colitis. Am J Gastroenterol. 1992 Oct;87(10):1447–1452. [PubMed] [Google Scholar]
- Katakura S., Reinholt F. P., Kärnell A., Huan P. T., Trach D. D., Lindberg A. A. The pathology of Shigella flexneri infection in rhesus monkeys: an endoscopic and histopathological study of colonic lesions. APMIS. 1990 Apr;98(4):313–319. doi: 10.1111/j.1699-0463.1990.tb01038.x. [DOI] [PubMed] [Google Scholar]
- Klimpel G. R., Shaban R., Niesel D. W. Bacteria-infected fibroblasts have enhanced susceptibility to the cytotoxic action of tumor necrosis factor. J Immunol. 1990 Jul 15;145(2):711–717. [PubMed] [Google Scholar]
- Kärnell A., Reinholt F. P., Katakura S., Lindberg A. A. Shigella flexneri infection: a histopathologic study of colonic biopsies in monkeys infected with virulent and attenuated bacterial strains. APMIS. 1991 Sep;99(9):787–796. doi: 10.1111/j.1699-0463.1991.tb01261.x. [DOI] [PubMed] [Google Scholar]
- Labrec E. H., Schneider H., Magnani T. J., Formal S. B. EPITHELIAL CELL PENETRATION AS AN ESSENTIAL STEP IN THE PATHOGENESIS OF BACILLARY DYSENTERY. J Bacteriol. 1964 Nov;88(5):1503–1518. doi: 10.1128/jb.88.5.1503-1518.1964. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Louise C. B., Obrig T. G. Shiga toxin-associated hemolytic-uremic syndrome: combined cytotoxic effects of Shiga toxin, interleukin-1 beta, and tumor necrosis factor alpha on human vascular endothelial cells in vitro. Infect Immun. 1991 Nov;59(11):4173–4179. doi: 10.1128/iai.59.11.4173-4179.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Luo G., Niesel D. W., Shaban R. A., Grimm E. A., Klimpel G. R. Tumor necrosis factor alpha binding to bacteria: evidence for a high-affinity receptor and alteration of bacterial virulence properties. Infect Immun. 1993 Mar;61(3):830–835. doi: 10.1128/iai.61.3.830-835.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Mathan V. I., Penny G. R., Mathan M. M., Rowley D. Bacterial lipopolysaccharide-induced intestinal microvascular lesions leading to acute diarrhea. J Clin Invest. 1988 Nov;82(5):1714–1721. doi: 10.1172/JCI113785. [DOI] [PMC free article] [PubMed] [Google Scholar]
- McCabe R. P., Secrist H., Botney M., Egan M., Peters M. G. Cytokine mRNA expression in intestine from normal and inflammatory bowel disease patients. Clin Immunol Immunopathol. 1993 Jan;66(1):52–58. doi: 10.1006/clin.1993.1007. [DOI] [PubMed] [Google Scholar]
- Mitsuyama K., Sasaki E., Toyonaga A., Ikeda H., Tsuruta O., Irie A., Arima N., Oriishi T., Harada K., Fujisaki K. Colonic mucosal interleukin-6 in inflammatory bowel disease. Digestion. 1991;50(2):104–111. doi: 10.1159/000200747. [DOI] [PubMed] [Google Scholar]
- Movat H. Z., Burrowes C. E., Cybulsky M. I., Dinarello C. A. Acute inflammation and a Shwartzman-like reaction induced by interleukin-1 and tumor necrosis factor. Synergistic action of the cytokines in the induction of inflammation and microvascular injury. Am J Pathol. 1987 Dec;129(3):463–476. [PMC free article] [PubMed] [Google Scholar]
- Nicholls S., Stephens S., Braegger C. P., Walker-Smith J. A., MacDonald T. T. Cytokines in stools of children with inflammatory bowel disease or infective diarrhoea. J Clin Pathol. 1993 Aug;46(8):757–760. doi: 10.1136/jcp.46.8.757. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Noronha I. L., Weis H., Hartley B., Wallach D., Cameron J. S., Waldherr R. Expression of cytokines, growth factors, and their receptors in renal allograft biopsies. Transplant Proc. 1993 Feb;25(1 Pt 2):917–918. [PubMed] [Google Scholar]
- Olofsson A., Miyazono K., Kanzaki T., Colosetti P., Engström U., Heldin C. H. Transforming growth factor-beta 1, -beta 2, and -beta 3 secreted by a human glioblastoma cell line. Identification of small and different forms of large latent complexes. J Biol Chem. 1992 Sep 25;267(27):19482–19488. [PubMed] [Google Scholar]
- Pullman W. E., Elsbury S., Kobayashi M., Hapel A. J., Doe W. F. Enhanced mucosal cytokine production in inflammatory bowel disease. Gastroenterology. 1992 Feb;102(2):529–537. doi: 10.1016/0016-5085(92)90100-d. [DOI] [PubMed] [Google Scholar]
- Romagnani S. Human TH1 and TH2 subsets: regulation of differentiation and role in protection and immunopathology. Int Arch Allergy Immunol. 1992;98(4):279–285. doi: 10.1159/000236199. [DOI] [PubMed] [Google Scholar]
- Sander B., Andersson J., Andersson U. Assessment of cytokines by immunofluorescence and the paraformaldehyde-saponin procedure. Immunol Rev. 1991 Feb;119:65–93. doi: 10.1111/j.1600-065x.1991.tb00578.x. [DOI] [PubMed] [Google Scholar]
- Schmitz J., Assenmacher M., Radbruch A. Regulation of T helper cell cytokine expression: functional dichotomy of antigen-presenting cells. Eur J Immunol. 1993 Jan;23(1):191–199. doi: 10.1002/eji.1830230130. [DOI] [PubMed] [Google Scholar]
- Singer I. I., Scott S., Hall G. L., Limjuco G., Chin J., Schmidt J. A. Interleukin 1 beta is localized in the cytoplasmic ground substance but is largely absent from the Golgi apparatus and plasma membranes of stimulated human monocytes. J Exp Med. 1988 Feb 1;167(2):389–407. doi: 10.1084/jem.167.2.389. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Stevens C., Walz G., Singaram C., Lipman M. L., Zanker B., Muggia A., Antonioli D., Peppercorn M. A., Strom T. B. Tumor necrosis factor-alpha, interleukin-1 beta, and interleukin-6 expression in inflammatory bowel disease. Dig Dis Sci. 1992 Jun;37(6):818–826. doi: 10.1007/BF01300378. [DOI] [PubMed] [Google Scholar]
- Takeuchi A., Formal S. B., Sprinz H. Exerimental acute colitis in the Rhesus monkey following peroral infection with Shigella flexneri. An electron microscope study. Am J Pathol. 1968 Mar;52(3):503–529. [PMC free article] [PubMed] [Google Scholar]
- Tesh V. L., Samuel J. E., Perera L. P., Sharefkin J. B., O'Brien A. D. Evaluation of the role of Shiga and Shiga-like toxins in mediating direct damage to human vascular endothelial cells. J Infect Dis. 1991 Aug;164(2):344–352. doi: 10.1093/infdis/164.2.344. [DOI] [PubMed] [Google Scholar]
- de Silva D. G., Mendis L. N., Sheron N., Alexander G. J., Candy D. C., Chart H., Rowe B. Concentrations of interleukin 6 and tumour necrosis factor in serum and stools of children with Shigella dysenteriae 1 infection. Gut. 1993 Feb;34(2):194–198. doi: 10.1136/gut.34.2.194. [DOI] [PMC free article] [PubMed] [Google Scholar]