title: ATP conditions intestinal epithelial cells to an inflammatory state that promotes components of DC maturation.
abstract: Intestinal epithelial cells (IECs) normally promote the development of gut resident tolerogenic dendritic cells (DCs) and regulatory T cells, but how this process is altered in inflammatory bowel disease is not well characterized. Recently, we published that the cell injury signal ATP modulates IEC chemokine responses to the TLR5 ligand flagellin and exacerbates colitis in the presence of flagellin. We hypothesized that ATP switches these IECs from tolerogenic to proinflammatory, enhancing DC activation and immune responses to commensal antigens. Here, we report that ATP enhanced murine IEC production of KC, IL-6, TGF-β, and thymic stromal lymphopoietin in response to TLR1/2 stimulation by Pam(3) CSK(4)  (PAM). Moreover, supernatants from IECs stimulated with ATP+PAM enhanced expression of CD80 on bone marrow derived dendritic cells, and increased their production of IL-12, IL-6, IL-23, TGF-β, and aldh1a2, suggesting a Th1/Th17 polarizing environment. DCs conditioned by stressed IECs stimulated an enhanced recall response to flagellin and supported the expansion of IFN-γ(+)  and IL-17(+)  memory T cells. Lastly, colonic administration of nonhydrolysable ATP increased production of IL-6 and Cxcl1 (KC) by IECs. These findings indicate that ATP influences the response of IECs to TLR ligands and biases the maturation of DCs to become inflammatory.
authors.affiliation: Department of Medicine, University of British Columbia and Vancouver Coastal Health Research Institute, Vancouver, BC, Canada.
authors.forename: Yu
authors.initials: Y
authors.lastname: Yao
authors.forename: Megan K
authors.initials: MK
authors.lastname: Levings
authors.forename: Theodore S
authors.initials: TS
authors.lastname: Steiner
mesh_terms: D000255:Adenosine Triphosphate / Q000494:pharmacology*; D000818:Animals; D002478:Cells, Cultured; D017077:Culture Media, Conditioned / Q000494:pharmacology; D016207:Cytokines / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology* / Q000473:pathology; D004847:Epithelial Cells / Q000276:immunology* / Q000473:pathology; D005408:Flagellin / Q000276:immunology / Q000494:pharmacology; D007249:Inflammation / Q000276:immunology / Q000473:pathology; D007413:Intestinal Mucosa / Q000276:immunology* / Q000473:pathology; D055666:Lipopeptides / Q000276:immunology / Q000494:pharmacology; D051379:Mice; D008822:Mice, Transgenic; D018417:Th1 Cells / Q000276:immunology / Q000473:pathology; D058504:Th17 Cells / Q000276:immunology / Q000473:pathology; D051198:Toll-Like Receptor 5 / Q000819:agonists / Q000276:immunology
chemical_list: D017077:Culture Media, Conditioned; D016207:Cytokines; D055666:Lipopeptides; C508075:Pam(3)CSK(4) peptide; D051198:Toll-Like Receptor 5; D005408:Flagellin; D000255:Adenosine Triphosphate