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Human Intestinal Epithelial Cells of Proinflammatory Cytokine The Regulation and Functional Consequence of Proinflammatory Cytokine Binding on Human Intestinal Epithelial Cells This information is current as Asit Panja, Stan Goldberg, Lars Eckmann, Priya Krishen and of September 27, 2021. Lloyd Mayer J Immunol 1998; 161:3675-3684; ; http://www.jimmunol.org/content/161/7/3675 Downloaded from References This article cites 63 articles, 19 of which you can access for free at: http://www.jimmunol.org/content/161/7/3675.full#ref-list-1 Why The JI? Submit online. http://www.jimmunol.org/ • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average by guest on September 27, 2021 Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 1998 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Regulation and Functional Consequence of Proinflammatory Cytokine Binding on Human Intestinal Epithelial Cells1 Asit Panja,2* Stan Goldberg,* Lars Eckmann,† Priya Krishen,* and Lloyd Mayer* Products of an activated immune system may affect cells within the immune system as well as nonlymphoid cells in the local environment. Given the immunologically activated state of the intestinal tract, it is conceivable that locally produced cytokines could regulate epithelial cell function. To assess whether epithelial cells are targets for particular cytokines, we initiated studies on the binding of a panel of proinflammatory cytokines in freshly isolated epithelial cells from normal and inflammatory bowel disease (IBD) patients as well as in cell lines. Isolated intestinal epithelial cells (IEC) were stained with phycoerythrin-conjugated b or biotinylated cytokines to determine the expression and density of receptors for IL-1 , IL-6, granulocyte-macrophage CSF Downloaded from (GM-CSF), and TNF-a. Receptors for IL-1b, IL-6, and GM-CSF were readily detectable in all epithelial cell preparations at levels equal to (GM-CSFR) or lower than those seen on monocytes. However TNFa-R were not detectable on freshly isolated IECs. Receptor density was greater in surface vs crypt epithelial cells, but no significant differences were seen between normal and IBD epithelial cells. Expression of IL-1R and IL-6R was enhanced by LPS and IFN-g. Functionally, IL-1b enhanced proliferation of the IEC cell line, DLD1, whereas GM-CSF treatment of de-differentiated crypt-like DLD1 and HT29 cells resulted in enhanced expression of ICAM-1. Furthermore, TNF-a treatment enhanced the secretion of IL-8 and GRO-a in HT29 cells, but not in freshly http://www.jimmunol.org/ isolated IEC cultures. The differential binding and function of proinflammatory cytokines on IEC support the hypothesis that these cytokines may be involved in normal physiological processes as well as in regulating mucosal immune responses. The Journal of Immunology, 1998, 161: 3675–3684. he pathophysiological mechanisms underlying the devel- propria lymphocytes (15–19) from inflammatory bowel disease opment of IBD are not fully understood. In ulcerative (IBD) patients. There is increasing evidence that intestinal epithe- T colitis (UC)3, the final target of the inflammatory process lial cells (IEC) may serve as targets for these locally produced appears to be the epithelium, and epithelial cell dysfunction has cytokines. In this scenario, local cytokines may result in alterations been demonstrated. In Crohn’s disease (CD), inflammation ex- of epithelial cell function or integrity. For example, the combina- by guest on September 27, 2021 tends transmurally, and the epithelium may be spared from de- tion of TNF-a and IFN-g is cytotoxic for the colonic epithelial cell struction. However, there is evidence that epithelial cell dysfunc- line, HT29 (20), and IL-1b up-regulates IL-6 synthesis (a proin- tion exists in this disease as well. Although separate cellular or flammatory cytokine) by epithelial cells (21). Alternatively or ad- molecular events may be involved in these inflammatory pro- ditionally, cytokines may play a role in the normal regulatory cesses, it has been widely accepted that locally produced cytokines mechanisms involved in epithelial cell growth and differentiation may play a critical role, comparable to their effects in a number of ensuring maintenance of homeostasis. An imbalance of the normal other chronic inflammatory disorders such as rheumatoid arthritis cytokine milieu seen in IBD might lead to the disruption of epi- (1–7), psoriasis (8), and glomerulonephritis (9, 10). Proinflamma- thelial function. There is evidence for selective effects of various tory cytokines such as IL-1, IL-6, granulocyte-macrophage CSF cytokines on IEC growth and differentiation, phenotype, and func- (GM-CSF), and TNF-a have been reported to be increased in se- tion through an autocrine/juxtacrine or paracrine pathway. One rum (11), cultures of biopsy tissues (12–14), or isolated lamina hypothetical model based on these scenarios might be that cyto- kine-mediated changes in the epithelial cell integrity might initiate pathologic events in the gut. The ability of cytokines to function in *Division of Clinical Immunology, Mount Sinai Medical Center, New York, NY this manner depends on the presence of specific receptors ex- 10029; and †Department of Medicine, University of California at San Diego, Lo Jolla, CA 92093 pressed on IECs. Therefore, we analyzed the binding of the proinflammatory cy- Received for publication October 23, 1997. Accepted for publication May 27, 1998. tokines IL-1b, IL-6, GM-CSF, and TNF-a on both freshly isolated The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance intestinal epithelial cells and cell lines by flow cytometric analysis. with 18 U.S.C. Section 1734 solely to indicate this fact. Our results show that IECs from both IBD and normal control 1 This work was supported by a First Award Grant (to A.P.) and a Career Develop- samples express receptors for GM-CSF, IL-1b, and IL-6 at com- ment Award (to L.E.) from the Crohn’s and Colitis Foundation of America and U.S. parable levels. TNFa-R were not detected on freshly isolated ep- Public Health Service Grants AI-23504, AI-24671, and DK-44156 (to L.M.). ithelial cells, although they were present on colonic adenocarci- 2 Present address, correspondence and reprint request to Dr. Asit Panja, Division of Gastroenterology, Hepatology and Nutrition, Winthrop University Hospital, 222 Sta- noma cell lines. Functionally, IL-1 enhanced while GM-CSF tion Plaza North, Suite 511A, Mineola, Long Island, New York 11501. inhibited IEC growth. Furthermore, GM-CSF could induce or up- 3 Abbreviations used in this paper: UC, ulcerative colitis; CD, Crohn’s disease; GM- regulate ICAM-1 expression preferentially on crypt-like epithelial CSF, granulocyte-macrophage CSF; IBD, inflammatory bowel disease; IEC, intestinal cells. Taken together, these results support the potential for an epithelial cell; MCF, mean channel fluorescence; PE, phycoerythrin; ECAM-1, en- dothelial cell adhesion molecule-1; ELAM-1, endothelial leukocyte adhesion autocrine or paracrine effect of proinflammatory and prophago- molecule-1. cytic cytokines as potential modulators of epithelial cell integrity. Copyright © 1998 by The American Association of Immunologists 0022-1767/98/$02.00 3676 CYTOKINE BINDING BY INTESTINAL EPITHELIAL CELLS Materials and Methods Cell lines Isolation of IEC Cell lines (EL-4, L929, DLD1, HT-29, and Caco2) were obtained from the American Type Culture Collection (ATCC; Manassas, VA). The IL-6 re- Epithelial cells from resected bowel specimens were isolated by dispase or sponsive plasmacytoma cell line B9, was kindly provided by Dr. Lester EDTA (TNFa-R) treatment as previously described (22, 23). Surgical May (New York Medical College, Valhalla, NY). Cell lines were either specimens included those from “normal” controls, i.e., patients with ade- used as positive controls for receptor assays or as sources of intestinal nocarcinoma (10 cm from tumor), colonic inertia, and familial polyposis, epithelium. Cells were thawed and grown in T75 tissue culture flasks as well as those from patients with active and inactive UC and CD. In the (Nunc, Naperville, IL). DLD1, HT29, and L-929 cell lines were grown in latter cases, tissues were obtained from both areas of active inflammation RPMI 1640 medium supplemented with 10% FCS (Life Technologies, and areas where no histologic inflammation was noted (where available). Gaithersburg, MD), Caco2 in DMEM with 10% FCS, EL-4 in DMEM with Briefly, after vigorous washing in PBS, the mucosal layer was dissected 10% horse serum, and B9 cells in RPMI 1640 with 10% FCS and 20 U/ml from the underlying submucosa. The dissected mucosal tissue was washed rIL-6 (kind gift of Dr. Edward Siden, Mount Sinai Medical Center, NY). several times in HBSS supplemented with 1% penicillin-streptomycin, am- All culture media contained 1% penicillin-streptomycin (ICN-Flow. photericin, and gentamicin (50 mg/ml), minced into small pieces, and fol- McLean, VA) and L-glutamine (ICN-Flow). Cells from suspension cultures lowed by treatment with the mucolytic agent DTT (1 mM) (Sigma, St. (EL-4, B9) or confluent monolayers (DLD1, HT29, Caco2), dissociated Louis, MO) in RPMI 1640 medium for 5 min at room temperature. Tissue from the plastic surface by treating with a nonenzymatic cell dissociation pieces were washed in PBS and subjected to dispase (1 mg/ml; Boehringer solution (Sigma), were washed and used for staining.
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