Lipopolysaccharide-induced human enterocyte tolerance to cytokine-mediated interleukin-8 production may occur independently of TLR-4/MD-2 signaling.
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-1beta) activated IL-8 response that occurs independently of TLR-4/MD-2 signaling. IL-8 production in response to activation by unrelated TNF-alpha 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.
Savidge
Tor C
TC
Developmental Gastroenterology Laboratory, MA General Hospital and Harvard Medical School, Charlestown 02129, USA.
Newman
Paul G
PG
Pan
Wei-Hua
WH
Weng
Mei-Qian
MQ
Shi
Hai Ning
HN
McCormick
Beth A
BA
Quaroni
Andrea
A
Walker
W Allan
WA
D016207:Cytokines / Q000494:pharmacology; D004751:Enteritis / Q000276:immunology; D020895:Enterocytes / Q000187:drug effects / Q000276:immunology*; D005786:Gene Expression Regulation; D006801:Humans; D007108:Immune Tolerance; D007375:Interleukin-1 / Q000378:metabolism; D016209:Interleukin-8 / Q000096:biosynthesis* / Q000235:genetics; D008070:Lipopolysaccharides / Q000276:immunology / Q000494:pharmacology*; D051218:Lymphocyte Antigen 96 / Q000378:metabolism*; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000378:metabolism*; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured
D016207:Cytokines; D007375:Interleukin-1; D016209:Interleukin-8; C495377:LY96 protein, human; D008070:Lipopolysaccharides; D051218:Lymphocyte Antigen 96; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4