Celia L Menckeberg1, Jeroen Hol2, Ytje Simons-Oosterhuis1, H Rolien C Raatgeep1, Lilian F de Ruiter3, Dicky J Lindenbergh-Kortleve1, Anita M Korteland-van Male1, Sahar El Aidy4, Pieter P E van Lierop1, Michiel Kleerebezem5, Michael Groeneweg6, Georg Kraal7, Beatrix E Elink-Schuurman8, Johan C de Jongste8, Edward E S Nieuwenhuis9, Janneke N Samsom1. 1. Laboratory of Pediatrics, Division of Gastroenterology and Nutrition, Erasmus MC, Rotterdam, The Netherlands. 2. Laboratory of Pediatrics, Division of Gastroenterology and Nutrition, Erasmus MC, Rotterdam, The Netherlands Department of Pulmonary Diseases, Sophia Children's Hospital, Rotterdam, The Netherlands Department of Pediatrics, University Hospital Ghent, Ghent, Belgium. 3. Laboratory of Pediatrics, Division of Gastroenterology and Nutrition, Erasmus MC, Rotterdam, The Netherlands Department of Pulmonary Diseases, Sophia Children's Hospital, Rotterdam, The Netherlands. 4. Laboratory of Microbiology and Host Microbe Interactomics Group, Wageningen University, Wageningen, The Netherlands Department of Industrial Biotechnology, GEBRI, Sadat City University, Sadat City, Egypt. 5. Laboratory of Microbiology and Host Microbe Interactomics Group, Wageningen University, Wageningen, The Netherlands. 6. Department of Pediatrics, Maasstad Hospital, Rotterdam, The Netherlands. 7. Department of Molecular Cell Biology and Immunology, VU University Medical Center, Amsterdam, The Netherlands. 8. Department of Pulmonary Diseases, Sophia Children's Hospital, Rotterdam, The Netherlands. 9. Laboratory of Pediatrics, Division of Gastroenterology and Nutrition, Erasmus MC, Rotterdam, The Netherlands Wilhelmina Children's Hospital, Utrecht, The Netherlands.
Abstract
OBJECTIVE: Repetitive interaction with microbial stimuli renders epithelial cells (ECs) hyporesponsive to microbial stimulation. Previously, we have reported that buccal ECs from a subset of paediatric patients with Crohn's disease are not hyporesponsive and spontaneously released chemokines. We now aimed to identify kinetics and mechanisms of acquisition of hyporesponsiveness to microbial stimulation using primary human buccal epithelium. DESIGN: Buccal ECs collected directly after birth and in later stages of life were investigated. Chemokine release and regulatory signalling pathways were studied using primary buccal ECs and the buccal EC line TR146. Findings were extended to the intestinal mucosa using murine model systems. RESULTS: Directly after birth, primary human buccal ECs spontaneously produced the chemokine CXCL-8 and were responsive to microbial stimuli. Within the first weeks of life, these ECs attained hyporesponsiveness, associated with inactivation of the NF-κB pathway and upregulation of the novel NF-κB inhibitor SLPI but no other known NF-κB inhibitors. SLPI protein was abundant in the cytoplasm and the nucleus of hyporesponsive buccal ECs. Knock-down of SLPI in TR146-buccal ECs induced loss of hyporesponsiveness with increased NF-κB activation and subsequent chemokine release. This regulatory mechanism extended to the intestine, as colonisation of germfree mice elicited SLPI expression in small intestine and colon. Moreover, SLPI-deficient mice had increased chemokine expression in small intestinal and colonic ECs. CONCLUSIONS: We identify SLPI as a new player in acquisition of microbial hyporesponsiveness by buccal and intestinal epithelium in the first weeks after microbial colonisation. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
OBJECTIVE: Repetitive interaction with microbial stimuli renders epithelial cells (ECs) hyporesponsive to microbial stimulation. Previously, we have reported that buccal ECs from a subset of paediatric patients with Crohn's disease are not hyporesponsive and spontaneously released chemokines. We now aimed to identify kinetics and mechanisms of acquisition of hyporesponsiveness to microbial stimulation using primary human buccal epithelium. DESIGN: Buccal ECs collected directly after birth and in later stages of life were investigated. Chemokine release and regulatory signalling pathways were studied using primary buccal ECs and the buccal EC line TR146. Findings were extended to the intestinal mucosa using murine model systems. RESULTS: Directly after birth, primary human buccal ECs spontaneously produced the chemokine CXCL-8 and were responsive to microbial stimuli. Within the first weeks of life, these ECs attained hyporesponsiveness, associated with inactivation of the NF-κB pathway and upregulation of the novel NF-κB inhibitor SLPI but no other known NF-κB inhibitors. SLPI protein was abundant in the cytoplasm and the nucleus of hyporesponsive buccal ECs. Knock-down of SLPI in TR146-buccal ECs induced loss of hyporesponsiveness with increased NF-κB activation and subsequent chemokine release. This regulatory mechanism extended to the intestine, as colonisation of germfree mice elicited SLPI expression in small intestine and colon. Moreover, SLPI-deficientmice had increased chemokine expression in small intestinal and colonic ECs. CONCLUSIONS: We identify SLPI as a new player in acquisition of microbial hyporesponsiveness by buccal and intestinal epithelium in the first weeks after microbial colonisation. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
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Keywords:
Bacterial Interactions; Epithelial Cells; Gut Immunology; IBD Basic Research
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