title: IRAK-M modulates expression of IL-10 and cell surface markers CD80 and MHC II after bacterial re-stimulation of tolerized dendritic cells.
abstract: BACKGROUND
  As essential components of the innate immune system, dendritic cells (DCs) can interact directly with pathogens as well as participate in the adaptive immune response. In cells closely related to DCs such as macrophages and monocytes, prior exposure to minute amounts of endotoxin can lead to a refractory period where subsequent exposure to higher doses fails to induce an inflammatory response; little research has investigated this effect on DCs. This study tested if murine bone marrow-derived dendritic cells (BM-DCs) respond to endotoxin- and bacterial sonicate-induced tolerance by decreased inflammatory and increased anti-inflammatory response, and the role of IRAK-M, an intracellular negative regulator of TLR signaling, in this tolerance.
  
  
  RESULTS
  Tolerized BM-DCs exhibited a significant drop in TNF-α and IL-12p70 production and increased IL-10 expression compared to untolerized cells. BM-DCs also showed the ability to develop heterotolerance, in which the LPS exposure alone was able to induce tolerance to Helicobacter pylori sonicate and TLR2 agonist Pam3Cys. Furthermore, the expression of IRAK-M was increased after restimulation of tolerized BM-DCs as determined qPCR and Western blot. IRAK-M exhibited a suppressive effect on surface expression of major histocompatibilty complex class II (MHC II) and CD80 in LPS-tolerized BM-DCs. IL-10 expression in bacterial sonicate-tolerized IRAK-M-/- BM-DCs was altered as compared to wild type BM-DCs, with tolerance-induced expression of IL-10 mitigated in tolerized IRAK-M-/- BM-DCs.
  
  
  CONCLUSIONS
  Along with endotoxin, bacterial sonicate is able to induce refractory tolerance in BM-DCs, and IRAK-M plays a role in modulating cell surface expression of MHC class II and CD80 and release of IL-10 during this tolerance.
authors.affiliation: Division of Gastroenterology, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, MI 48109, United States.
authors.forename: Tyler S
authors.initials: TS
authors.lastname: Cole
authors.forename: Min
authors.initials: M
authors.lastname: Zhang
authors.forename: Theodore J
authors.initials: TJ
authors.lastname: Standiford
authors.forename: Michael
authors.initials: M
authors.lastname: Newstead
authors.forename: Jay
authors.initials: J
authors.lastname: Luther
authors.forename: Jiajie
authors.initials: J
authors.lastname: Zhang
authors.forename: Chun-Chia
authors.initials: CC
authors.lastname: Chen
authors.forename: John Y
authors.initials: JY
authors.lastname: Kao
mesh_terms: D000818:Animals; D018122:B7-1 Antigen / Q000235:genetics / Q000378:metabolism*; D001854:Bone Marrow Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D004731:Endotoxins / Q000276:immunology; D004926:Escherichia coli / Q000276:immunology; D005786:Gene Expression Regulation; D006090:Gram-Negative Bacteria / Q000276:immunology*; D016480:Helicobacter pylori / Q000276:immunology; D000949:Histocompatibility Antigens Class II / Q000235:genetics / Q000378:metabolism; D007108:Immune Tolerance; D053592:Interleukin-1 Receptor-Associated Kinases / Q000235:genetics / Q000378:metabolism*; D016753:Interleukin-10 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL
chemical_list: D018122:B7-1 Antigen; D004731:Endotoxins; D000949:Histocompatibility Antigens Class II; C556062:IL10 protein, mouse; D016753:Interleukin-10; D053592:Interleukin-1 Receptor-Associated Kinases; C507772:Irak3 protein, mouse