title: The stress signal extracellular ATP modulates antiflagellin immune responses in intestinal epithelial cells.
abstract: BACKGROUND
  Although intestinal epithelial cells (IECs) are continually exposed to commensal microbes, under healthy conditions they contribute to intestinal homeostasis while keeping inflammatory responses in check. In response to invading pathogens, however, IECs respond vigorously by producing inflammatory mediators. To better understand the signals that regulate the inflammatory responses of IECs, we investigated whether the danger signal ATP (which is released from injured cells) could alter responses to bacterial products.
  
  
  METHODS
  We measured chemokine production from Caco-2 cells stimulated with the Toll-like receptor 5 agonist flagellin with or without ATP. ATP increased flagellin-induced IL-8 secretion but reduced CCL20 secretion via distinct signaling pathways.
  
  
  RESULTS
  ATP-enhanced IL-8 production was only partly blocked by the P(2) receptor antagonist suramin and required activation of NF-κB while ATP-mediated reduction of CCL20 was completely blocked by suramin and required activation of ERK1/2. The effects of ATP on both chemokines required extracellular calcium but not phospholipase C, implicating P(2) X receptor involvement. To investigate how ATP alters IEC responses to bacterial products in vivo, mice receiving dextran sodium sulfate were given intrarectal flagellin with or without ATP. Addition of ATP to flagellin caused greater weight loss and increased antiflagellin antibody titers, as well as decreased colonic interferon gamma (IFN-γ) and higher antiflagellin IgG1/IgG2 ratios, which indicate decreased Th1 polarization.
  
  
  CONCLUSIONS
  Together, these data indicate that stress, in the form of extracellular ATP, reshapes both the inflammatory response of flagellin-stimulated IECs and downstream adaptive immunity, representing a possible strategy by which these cells differentiate between commensal and pathogenic bacteria.
authors: Division of Infectious Diseases, Department of Medicine, University of British Columbia, Vancouver, BC, Canada. tsteiner@interchange.ubc.ca
authors: Sabine M
authors: SM
authors: Ivison
authors: Megan E
authors: ME
authors: Himmel
authors: Matt
authors: M
authors: Mayer
authors: Yu
authors: Y
authors: Yao
authors: Arnawaz
authors: A
authors: Kifayet
authors: Megan K
authors: MK
authors: Levings
authors: Theodore S
authors: TS
authors: Steiner
mesh_terms: D000255:Adenosine Triphosphate / Q000494:pharmacology*; D000818:Animals; D018938:Caco-2 Cells; D054418:Chemokine CCL20 / Q000235:genetics / Q000378:metabolism; D018925:Chemokines / Q000235:genetics / Q000378:metabolism; D003092:Colitis / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D024202:Electrophoretic Mobility Shift Assay; D004847:Epithelial Cells / Q000187:drug effects* / Q000276:immunology* / Q000378:metabolism; D005408:Flagellin / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D016209:Interleukin-8 / Q000378:metabolism; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000187:drug effects* / Q000276:immunology*; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D051198:Toll-Like Receptor 5 / Q000235:genetics / Q000378:metabolism
chemical_list: C108355:CCL20 protein, human; D054418:Chemokine CCL20; D018925:Chemokines; D016209:Interleukin-8; D016328:NF-kappa B; D012333:RNA, Messenger; D051198:Toll-Like Receptor 5; D005408:Flagellin; D000255:Adenosine Triphosphate