title: Intravenous immunoglobulin skews macrophages to an anti-inflammatory, IL-10-producing activation state.
abstract: Intravenous Ig is used to treat autoimmune or autoinflammatory disorders, but the mechanism by which it exerts its immunosuppressive activity is not understood completely. To examine the impact of intravenous Ig on macrophages, we compared cytokine production by LPS-activated macrophages in the presence and absence of intravenous Ig. Intravenous Ig treatment induced robust production of IL-10 in response to LPS, relative to LPS stimulation alone, and reduced production of proinflammatory cytokines. This anti-inflammatory, intravenous Ig-induced activation was sustained for 24 h but could only be induced if intravenous Ig were provided within 1 h of LPS stimulation. Intravenous Ig activation led to enhanced and prolonged activation of MAPKs, Erk1/2, p38, and Erk5, and inhibition of each reduced intravenous Ig-induced IL-10 production and suppression of IL-12/23p40. IL-10 production occurred rapidly in response to intravenous Ig + LPS and was sufficient to reduce proinflammatory IL-12/23p40 production in response to LPS. IL-10 induction and reduced IL-12/23p40 production were transcriptionally regulated. IL-10 played a direct role in reducing proinflammatory cytokine production by macrophages treated with intravenous Ig + LPS, as macrophages from mice deficient in the IL-10R β chain or in IL-10 were compromised in their ability to reduce proinflammatory cytokine production. Finally, intraperitoneal injection of intravenous Ig or intravenous Ig + LPS into mice activated macrophages to produce high levels of IL-10 during subsequent or concurrent LPS challenge, respectively. These findings identify IL-10 as a key anti-inflammatory mediator produced by intravenous Ig-treated macrophages and provide insight into a novel mechanism by which intravenous Ig may dampen down inflammatory responses in patients with autoimmune or autoinflammatory diseases.
authors.affiliation: *Division of Gastroenterology and Division of Oncology, Hematology, and Blood and Marrow Transplantation, Department of Pediatrics, Michael Cuccione Childhood Cancer Research Program, Child & Family Research Institute, British Columbia Children's Hospital, and the University of British Columbia, Vancouver, British Columbia, Canada; Department of Anesthesia and Perioperative Care, University of California at San Francisco, San Francisco, California, USA; and Division of Gastroenterology, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Lisa K
authors.initials: LK
authors.lastname: Kozicky
authors.affiliation: *Division of Gastroenterology and Division of Oncology, Hematology, and Blood and Marrow Transplantation, Department of Pediatrics, Michael Cuccione Childhood Cancer Research Program, Child & Family Research Institute, British Columbia Children's Hospital, and the University of British Columbia, Vancouver, British Columbia, Canada; Department of Anesthesia and Perioperative Care, University of California at San Francisco, San Francisco, California, USA; and Division of Gastroenterology, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Zheng Yu
authors.initials: ZY
authors.lastname: Zhao
authors.affiliation: *Division of Gastroenterology and Division of Oncology, Hematology, and Blood and Marrow Transplantation, Department of Pediatrics, Michael Cuccione Childhood Cancer Research Program, Child & Family Research Institute, British Columbia Children's Hospital, and the University of British Columbia, Vancouver, British Columbia, Canada; Department of Anesthesia and Perioperative Care, University of California at San Francisco, San Francisco, California, USA; and Division of Gastroenterology, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Susan C
authors.initials: SC
authors.lastname: Menzies
authors.affiliation: *Division of Gastroenterology and Division of Oncology, Hematology, and Blood and Marrow Transplantation, Department of Pediatrics, Michael Cuccione Childhood Cancer Research Program, Child & Family Research Institute, British Columbia Children's Hospital, and the University of British Columbia, Vancouver, British Columbia, Canada; Department of Anesthesia and Perioperative Care, University of California at San Francisco, San Francisco, California, USA; and Division of Gastroenterology, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Mario
authors.initials: M
authors.lastname: Fidanza
authors.affiliation: *Division of Gastroenterology and Division of Oncology, Hematology, and Blood and Marrow Transplantation, Department of Pediatrics, Michael Cuccione Childhood Cancer Research Program, Child & Family Research Institute, British Columbia Children's Hospital, and the University of British Columbia, Vancouver, British Columbia, Canada; Department of Anesthesia and Perioperative Care, University of California at San Francisco, San Francisco, California, USA; and Division of Gastroenterology, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Gregor S D
authors.initials: GS
authors.lastname: Reid
authors.affiliation: *Division of Gastroenterology and Division of Oncology, Hematology, and Blood and Marrow Transplantation, Department of Pediatrics, Michael Cuccione Childhood Cancer Research Program, Child & Family Research Institute, British Columbia Children's Hospital, and the University of British Columbia, Vancouver, British Columbia, Canada; Department of Anesthesia and Perioperative Care, University of California at San Francisco, San Francisco, California, USA; and Division of Gastroenterology, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Kevin
authors.initials: K
authors.lastname: Wilhelmsen
authors.affiliation: *Division of Gastroenterology and Division of Oncology, Hematology, and Blood and Marrow Transplantation, Department of Pediatrics, Michael Cuccione Childhood Cancer Research Program, Child & Family Research Institute, British Columbia Children's Hospital, and the University of British Columbia, Vancouver, British Columbia, Canada; Department of Anesthesia and Perioperative Care, University of California at San Francisco, San Francisco, California, USA; and Division of Gastroenterology, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Judith
authors.initials: J
authors.lastname: Hellman
authors.affiliation: *Division of Gastroenterology and Division of Oncology, Hematology, and Blood and Marrow Transplantation, Department of Pediatrics, Michael Cuccione Childhood Cancer Research Program, Child & Family Research Institute, British Columbia Children's Hospital, and the University of British Columbia, Vancouver, British Columbia, Canada; Department of Anesthesia and Perioperative Care, University of California at San Francisco, San Francisco, California, USA; and Division of Gastroenterology, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Naomi
authors.initials: N
authors.lastname: Hotte
authors.affiliation: *Division of Gastroenterology and Division of Oncology, Hematology, and Blood and Marrow Transplantation, Department of Pediatrics, Michael Cuccione Childhood Cancer Research Program, Child & Family Research Institute, British Columbia Children's Hospital, and the University of British Columbia, Vancouver, British Columbia, Canada; Department of Anesthesia and Perioperative Care, University of California at San Francisco, San Francisco, California, USA; and Division of Gastroenterology, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Karen L
authors.initials: KL
authors.lastname: Madsen
authors.affiliation: *Division of Gastroenterology and Division of Oncology, Hematology, and Blood and Marrow Transplantation, Department of Pediatrics, Michael Cuccione Childhood Cancer Research Program, Child & Family Research Institute, British Columbia Children's Hospital, and the University of British Columbia, Vancouver, British Columbia, Canada; Department of Anesthesia and Perioperative Care, University of California at San Francisco, San Francisco, California, USA; and Division of Gastroenterology, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada laurasly@mail.ubc.ca.
authors.forename: Laura M
authors.initials: LM
authors.lastname: Sly
mesh_terms: D000818:Animals; D048049:Extracellular Signal-Regulated MAP Kinases / Q000276:immunology; D006801:Humans; D016756:Immunoglobulins, Intravenous / Q000494:pharmacology*; D016753:Interleukin-10 / Q000276:immunology*; D053762:Interleukin-12 Subunit p40 / Q000276:immunology; D008070:Lipopolysaccharides / Q000633:toxicity; D008262:Macrophage Activation / Q000187:drug effects*; D017737:Macrophages, Peritoneal / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D053701:Receptors, Interleukin-10 / Q000276:immunology
chemical_list: C556062:IL10 protein, mouse; D016756:Immunoglobulins, Intravenous; D053762:Interleukin-12 Subunit p40; D008070:Lipopolysaccharides; D053701:Receptors, Interleukin-10; D016753:Interleukin-10; D048049:Extracellular Signal-Regulated MAP Kinases
keywords: Fc receptors; macrophage activation; map kinases; regulatory macrophages; sepsis