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INTESTINAL INFECTION |
1 Laboratory of Gastrointestinal Immunology, Division of Gastroenterology, Department of Paediatrics, Children’s Hospital Medical Centre, University of Bonn, Bonn, Germany
2 INSERM EMI 0212, Paediatric Gastroenterology, Hôpital Necker Enfants malades, University of Paris V, Paris, France
3 Department of Anatomy and Cell Biology, University of Sherbrooke, Sherbrooke, Canada
4 Mucosal Immunology Laboratory, Division of Gastroenterology and Nutrition, Department of Pediatrics, Ste Justine Hospital, University of Montreal, Montreal, Quebec, Canada
Correspondence to:
Correspondence to:
Dr F M Ruemmele, Hôpital Necker-Enfants malades, Paediatric Gastroenterology, INSERM EMI 0212, University Paris V, 149, Rue de Sévres, F-75743 Paris, Cedex 15, France;
ruemmele{at}necker.fr
ABSTRACT
Background: Circulating levels of endotoxin (or lipopolysaccharide (LPS)) and anti-endotoxin antibodies are increased in patients with inflammatory bowel disease, supporting the hypothesis of a role for endogenous bacterial products in the pathogenesis of these disorders.
Aim: The aim of this study was to analyse the direct effects of LPS on intestinal epithelial cell turnover.
Methods and Results: LPS significantly inhibited growth of the human non-transformed immature crypt cell line (HIEC), whereas IEC-6 cell proliferation was stimulated by LPS. As LPS is a physiological inducer of tumour necrosis factor 
(TNF) in various cell systems and this cytokine exerted similar anti-proliferative (HIEC) or growth stimulatory (IEC-6 cells) effects, the study thus tested the hypothesis that endogenously produced TNF in response to LPS mediates this growth modulatory effect in an autoparacrine/paracrine way. Therefore, during LPS stimulation, the biological activity of TNF was blocked using neutralising anti-TNF antibodies, as well as inhibitory, antagonistic antibodies directed against the p55 TNF receptor, signalling the antimitotic TNF effect in HIEC. Both experimental approaches completely abolished the growth modulatory effects of LPS in HIEC/IEC-6 cells. Production and secretion of TNF by HIEC/IEC-6 cells in response to LPS was confirmed on mRNA and protein level by reverse transcription polymerase chain reaction (RT-PCR) and enzyme linked immunosorbent assay. LPS signalling was independent of CD14 in HIEC, as these cells lack this receptor. However, HIEC expressed TLR4 and MD2 resulting in a fully functional signalling complex as demonstrated by RT-PCR, western blot, and immunofluorescence analyses.
Conclusion: These results support the hypothesis that LPS induced changes of intestinal epithelial cell turnover may directly contribute to the pathogenesis of inflammatory epithelial cell lesions by endogenous TNF production by enterocytes.
Keywords: enterocytes; lipopolysaccharide; proliferation; toll-like receptors; tumour necrosis factor
Abbreviations: IBD, inflammatory bowel disease; CD, Crohn’s disease; UC, ulcerative colitis; LPS, lipopolysaccharide; IL, interleukin; TLR, toll-like receptors; IEC, intestinal epithelial cells; FCS, fetal calf serum; DNEM, Dulbecco’s modified Eagle’s medium; CHX, cycloheximide
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