title: Hypo-responsiveness of interleukin-8 production in human embryonic epithelial intestine 407 cells independent of NF-kappaB pathway: new lessons from endotoxin and ribotoxic deoxynivalenol.
abstract: Mucosal epithelium senses external toxic insults and transmits the danger signals into the epithelial cells in order to activate a broad range of inflammatory responses. However, pre-exposure to the commensal endotoxins can induce inflammatory tolerance and maintain the homeostasis without excessive immune responses. We recently reported that ribotoxin deoxynivalenol (DON) and its derivatives elicited the pro-inflammatory response as the mucosal insults in human epithelial cells. Taking the knowledge into consideration, we tested the hypothesis that endotoxin pre-exposure can attenuate ribotoxin-induced epithelial interleukin-8 (IL-8) production via a tolerance mechanism. Pre-exposure to endotoxin repressed IL-8 release and its gene expression. However, inflammatory tolerance was not mediated by the attenuated NF-kappaB activation which has been generally recognized as the major mediator of LPS-mediated toll-like receptor (TLR) signaling pathway. Instead, pre-exposure to endotoxin was observed to trigger the delayed induction of peroxisome proliferator-activated receptor gamma (PPAR-gamma) which contributed to the diminished IL-8 production in the human epithelial cells. Moreover, endogenous PPAR-gamma agonist suppressed toxicant-mediated interleukin-8 production and IL-8 mRNA stability. Taken together, endotoxin induced hypo-production of pro-inflammatory cytokine IL-8 in the human epithelial cells, which was associated with the delayed activation of PPAR-gamma expression by pre-existing endotoxin.
authors.affiliation: Department of Microbiology and Immunology, Medical Research Institute, Pusan National University School of Medicine, Busan 602-739, Korea. moon@pusan.ac.kr
authors.forename: Yuseok
authors.initials: Y
authors.lastname: Moon
authors.forename: Hyun
authors.initials: H
authors.lastname: Yang
authors.forename: Seung-Hwan
authors.initials: SH
authors.lastname: Park
mesh_terms: D015153:Blotting, Western; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D051766:Early Growth Response Protein 1 / Q000235:genetics; D004731:Endotoxins / Q000633:toxicity*; D004847:Epithelial Cells / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000096:biosynthesis / Q000235:genetics; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases / Q000378:metabolism; D006801:Humans; D007202:Indicators and Reagents; D016209:Interleukin-8 / Q000096:biosynthesis* / Q000235:genetics; D007413:Intestinal Mucosa / Q000378:metabolism*; D008156:Luciferases / Q000235:genetics; D016328:NF-kappa B / Q000235:genetics / Q000502:physiology*; D047495:PPAR gamma / Q000235:genetics / Q000502:physiology; D010957:Plasmids / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000502:physiology; D014162:Transfection; D014255:Trichothecenes / Q000633:toxicity*
chemical_list: C497325:EGR1 protein, human; D051766:Early Growth Response Protein 1; D004731:Endotoxins; D007202:Indicators and Reagents; D016209:Interleukin-8; D016328:NF-kappa B; D047495:PPAR gamma; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D014255:Trichothecenes; D008156:Luciferases; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases; D048049:Extracellular Signal-Regulated MAP Kinases; C007262:deoxynivalenol