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Human Intestinal Epithelial Cells Secrete Interleukin-1 Receptor

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Human Intestinal Epithelial Cells Secrete Interleukin-1 Receptor 350 Gut 2000;46:350–358 Human intestinal epithelial cells secrete interleukin-1 receptor antagonist and Gut: first published as 10.1136/gut.46.3.350 on 1 March 2000. Downloaded from interleukin-8 but not interleukin-1 or interleukin-6 R Daig, G Rogler, E Aschenbrenner, D Vogl, W Falk, V Gross, J Schölmerich, T Andus Abstract The classical functions of the intestinal epithe- Background—There is growing evidence lium are absorption and secretion of fluids, that intestinal epithelial cells (IECs) are electrolytes, and nutrients. Furthermore, the involved in the mucosal immune system. intestinal epithelial cells (IECs) form the Aim—To assess the pattern of cytokines primary physiological barrier against poten- secreted by IECs and lamina propria tially pathogenic microorganisms and a multi- mononuclear cells (LPMNCs). To achieve tude of antigens in the gut lumen. Damage of this, the expression and secretion of inter- the epithelial barrier is followed by bacterial leukin (IL)-1, IL-1 receptor antagonist invasion and inflammation of the mucosa. (IL-1ra), IL-6, and IL-8 in human pri- In addition, during the last few years more mary colonic and ileal IECs and LPMNCs and more data have accumulated showing that from the same patient were studied. IECs play an active role in the intestinal Methods—IECs and LPMNCs were iso- immune system. They express HLA-DR after lated from surgical specimens or endo- stimulation with interferon-ã.1–5 After stimula- scopic biopsy samples. mRNA expression tion with interferon or interleukin (IL)-1, they was investigated by northern blot analysis. show enhanced expression of adhesion Secretion of IL-1â, IL-6, IL-8, and IL-1ra molecules—for example, intercellular adhesion was measured by enzyme linked immuno- molecule-16 and lymphocyte function associ- sorbent assay. ated antigen (CD58).7 Intercellular adhesion Results—IL-1ra mRNA levels were higher molecule-1 could be enhanced in HT-29 and in IECs than in LPMNCs in all probands. Caco-2 cells by incubation with inflammatory IL-8 mRNA was only present in low cytokines; however, the responsiveness to http://gut.bmj.com/ amounts in the IECs from two controls. In interferon-á, tumour necrosis factor (TNF)-á, none of the specimens were IL-1â and IL-6 or IL-1 treatment was diVerent in the two cell mRNA present in IECs. Transcripts en- lines.8 Furthermore, evidence was found that coding IL-1â, IL-1ra, IL-6, and IL-8 were epithelial cells are able to respond to damage or identified in LPMNC preparations of all bacterial invasion by secreting cytokines.9–18 specimens. IECs from normal mucosa The cytokines reported to be secreted by IECs produced no detectable amounts of IL-1â are important inflammatory mediators such as or IL-6, whereas LPMNCs did. IECs IL-1, IL-6, and IL-8.19–21 To characterise on September 28, 2021 by guest. Protected copyright. secreted some IL-8 (65 (9) pg/105 cells) further the participation in the mucosal but significantly more was generated by immune system and the immunomodulatory LPMNCs (408 (43) pg/105 cells, p<0.0001). function of the intestinal epithelium, in vitro However, IECs secreted more IL-1ra than studies were performed. Cytokine production did LPMNCs (120 (12) v 94 (11) pg/105 has been studied in human and rat epithelial cells). In acute inflammation, IEC IL-1ra cell lines such as Caco-2, HT-29, and 18 22–24 secretion was significantly increased. A IEC-6. T84, HT-29,and SW620 cell lines secreted substantial amounts of IL-8 after Department of correlation between secreted IL-1ra and Internal Medicine I, the macroscopical degree of inflammation stimulation with IL-1â, TNF-á or interferon-ã, University of was found in Crohn’s disease (r = 0.64, but Caco-2 cells responded only to IL-1â.In Regensburg, Germany p<0.0001, n = 36) and ulcerative colitis (r = addition to theses cytokines, bacterial lipopoly- R Daig 0.76, p<0.0001, n = 24). saccharide was eYcient in stimulating IL-8 G Rogler Conclusions—IECs from normal mucosa release in SW620 and HT29 cells, whereas E Aschenbrenner T84 and Caco-2 cells were almost unrespon- D Vogl express and secrete IL-1ra and low 23 W Falk amounts of IL-8, but no IL-1 or IL-6. In sive to it. We showed that the synthesis of IL-8 V Gross in HT-29 cells was stimulated by IL-1â or inflamed mucosa the secretion of IL-1ra 22 J Schölmerich by IECs is slightly increased but may be TNF-á. These data indicate that the use of T Andus not suYcient to antagonise the greatly diVerent IEC lines may lead to diVerent results Correspondence to: increased production of proinflammatory Professor T Andus, cytokines by LPMNCs and the IECs Department of Internal themselves. Abbreviations used in this paper: IEC, intestinal Medicine I, University of ( 2000; :350–358) Regensburg, 93042 Gut 46 epithelial cell; LPMNC, lamina propria mononuclear Regensburg, Germany cell; IL, interleukin; IL-1ra, IL-1 receptor antagonist; Keywords: intestinal epithelial cells; lamina propria ELISA, enzyme linked immunosorbent assay; TNF, Accepted for publication mononuclear cells; mucosa; cytokines; interleukin; tumour necrosis factor; IBD, inflammatory bowel 9 September 1999 immune system disease; PBS, phosphate buVered saline. Intestinal epithelial cells in mucosal immune system 351 and diVerent interpretations of their immuno- and friability of the mucosa in ulcerative colitis; logical function. single small aphthous lesions in Crohn’s Several studies with epithelial cell lines have disease); ++ = moderate inflammation (mu- shown IL-6 secretion by IECs. Experiments cous membranes, spontaneous bleeding, and Gut: first published as 10.1136/gut.46.3.350 on 1 March 2000. Downloaded from with the rat-derived IEC-6 cell line suggested small ulcers in ulcerative colitis; multiple that IECs could represent an important source aphthous lesions, and small ulcers in Crohn’s of IL-6 in inflammatory responses at the intes- disease); +++ = severe inflammation (large tinal mucosa and that transforming growth ulcers in ulcerative colitis; large ulcerous factor-â could potentiate this function.24 A lesions in Crohn’s disease). recent study showed IL-1 induced and NF-êB Colitis was regarded as non-specific when mediated IL-6 production in Caco-2 cells.25 histological examination showed inflammatory Salmonella typhi has been shown to stimulate infiltrates in the mucosa that were not typical of IL-6 secretion in the small intestine epithelial IBD, and treatment with antibiotics led to cell line Int407.26 However, in a study using in complete restitution. Stool cultures from these situ hybridisation of human mucosa, IL-6 patients did not show any specific pathogen mRNA was not found in the epithelial cells and were negative for Clostridium diYcile toxin. except in one patient.27 In addition, in murine The study was approved by the ethics intestine, IL-6 mRNA was not located in the committee of the University of Regensburg and epithelial cell layer.28 performed in accordance with the declaration Recently we and others showed an imbal- of Helsinki. ance of the IL-1 system in colonic mucosa dur- 29 30 ing inflammation. IL-1á and IL-1â were ISOLATION OF COLONIC AND ILEAL EPITHELIAL significantly increased in the inflamed mucosa CELLS from patients with inflammatory bowel disease A method for the isolation of viable epithelial (IBD) and also in that from non-IBD patients cell preparation has been developed based on compared with healthy controls.29 The ratio of standard protocols and is described in more IL-1(á+â) to IL-1 receptor antagonist (IL-ra) detail elsewhere.32 In brief, mucosa was was significantly decreased, leading to a change stripped from submucosa within 30 minutes of in the balance of proinflammatory and anti- bowel resection and rinsed several times with inflammatory cytokines. IL-8 mRNA detected phosphate buVered saline (PBS). The mucus by in situ hybridisation was also increased in was removed by treatment with 1 mM inflamed colonic mucosa.31 The signal for IL-8 dithiothreitol (Serva, Heidelberg, Germany) could only be found in the lamina propria, for 15 minutes. After being washed with PBS, indicating intestinal macrophages as the major the mucosa was placed in 1.5 mM EDTA in source of IL-8. Therefore we concluded that Hanks balanced salt solution without calcium IL-8 is mainly produced in inflammatory cells and magnesium and tumbled for 10 minutes at http://gut.bmj.com/ in the lamina propria of the colon in IBD and 37°C. This supernatant containing debris and correlates with mucosal inflammation.31 These mainly villus cells was discarded. The mucosa results were in contrast with our findings in was incubated again with EDTA for 10 HT-29 cells, which responded to stimulation minutes at 37°C. The supernatant was col- with IL-8 secretion.22 lected into a 15 ml tube. Then the remaining As cell lines dediVerentiate in culture, we mucosa was vortex-mixed in PBS and this developed a culture system for primary cul- supernatant was also collected. It contained 32 tures of human IECs. Using this new system, complete crypts, some single cells, and a small on September 28, 2021 by guest. Protected copyright. we were able for the first time to compare the amount of debris. To separate IECs (crypts) expression and secretion of cytokines by IECs from contaminating non-epithelial cells, the and the corresponding lamina propria mono- suspension was allowed to sediment for 15 nuclear cells (LPMNCs) from the same minutes. The cells (mainly complete crypts) patient. were collected and washed twice with PBS. The procedure to isolate IECs from mucosal Materials and methods biopsy specimens was identical except that the PATIENTS dithiothreitol treatment was omitted.
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