Abstract
Intestinal epithelial cells (IEC) are constantly exposed to bacterial components, such as LPS, without triggering proinflammatory immune responses. This study demonstrates that chronic exposure of human-derived IEC to LPS induces tolerance to an endogenous inflammatory cytokine (IL-1β) activated IL-8 response that occurs independently of TLR-4/MD-2 signaling. IL-8 production in response to activation by unrelated TNF-α and PMA signaling pathways is also inhibited, indicating a broad-spanning tolerance. Quantitative rtPCR and IL-8 promoter-luciferase assays demonstrate that tolerance is regulated at the transcriptional level and occurs independently of IEC cytodifferentiation. By contrast, LPS does not significantly alter other proinflammatory signaling cascades in IEC that function independently of IL-8 production, e.g., IL-6 secretion and PEEC (Hepoxilin A3)-induced neutrophil transepithelial migration in response to invasive Salmonella typhimurium. Human IEC have therefore developed LPS-induced signaling cascades that promote an IL-8 hyporesponsiveness to proinflammatory cytokines while LPS exposure does not compromise the ability of IEC to mount other proinflammatory immune responses to invasive enteropathogens.
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Abbreviations
- DPPIV:
-
dipeptidylpeptidase IV
- fMLP:
-
n-formylmethionyl leucyl phenylalanine
- GI:
-
gastrointestinal
- IEC:
-
intestinal epithelial cell
- IRAK:
-
IL-1R-associated kinase
- LTA:
-
lipoteichoic acid
- PEEC:
-
pathogen-elicited epithelial chemosattractant
- PMN:
-
polymorphonucleocyte
- TLR:
-
toll-like receptor
- tsFHI:
-
temperature sensitive fetal human intestinal epithelial cells
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Acknowledgements
The authors thank Dr. B. Cherayil for helpful discussion and critical reviewing of this manuscript and Dr A. Keates for providing IL-8 promoter constructs.
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This study is supported by grants from the Crohn's and Colitis Foundation and the National Institutes of Health (RO1 DK70260; R37 HD12437; PO1 DK33506; P30 DK40561)
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Savidge, T., Newman, P., Pan, WH. et al. Lipopolysaccharide-Induced Human Enterocyte Tolerance to Cytokine-Mediated Interleukin-8 Production May Occur Independently of TLR-4/MD-2 Signaling. Pediatr Res 59, 89–95 (2006). https://doi.org/10.1203/01.pdr.0000195101.74184.e3
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DOI: https://doi.org/10.1203/01.pdr.0000195101.74184.e3
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