title: Differential Production of Type I IFN Determines the Reciprocal Levels of IL-10 and Proinflammatory Cytokines Produced by C57BL/6 and BALB/c Macrophages.
abstract: Pattern recognition receptors detect microbial products and induce cytokines, which shape the immunological response. IL-12, TNF-α, and IL-1β are proinflammatory cytokines, which are essential for resistance against infection, but when produced at high levels they may contribute to immunopathology. In contrast, IL-10 is an immunosuppressive cytokine, which dampens proinflammatory responses, but it can also lead to defective pathogen clearance. The regulation of these cytokines is therefore central to the generation of an effective but balanced immune response. In this study, we show that macrophages derived from C57BL/6 mice produce low levels of IL-12, TNF-α, and IL-1β, but high levels of IL-10, in response to TLR4 and TLR2 ligands LPS and Pam3CSK4, as well as Burkholderia pseudomallei, a Gram-negative bacterium that activates TLR2/4. In contrast, macrophages derived from BALB/c mice show a reciprocal pattern of cytokine production. Differential production of IL-10 in B. pseudomallei and LPS-stimulated C57BL/6 and BALB/c macrophages was due to a type I IFN and ERK1/2-dependent, but IL-27-independent, mechanism. Enhanced type I IFN expression in LPS-stimulated C57BL/6 macrophages was accompanied by increased STAT1 and IFN regulatory factor 3 activation. Furthermore, type I IFN contributed to differential IL-1β and IL-12 production in B. pseudomallei and LPS-stimulated C57BL/6 and BALB/c macrophages via both IL-10-dependent and -independent mechanisms. These findings highlight key pathways responsible for the regulation of pro- and anti-inflammatory cytokines in macrophages and reveal how they may differ according to the genetic background of the host.
authors.affiliation: Laboratory of Immunoregulation and Infection, The Francis Crick Institute, Mill Hill Laboratory, London NW7 1AA, United Kingdom;
authors.forename: Ashleigh
authors.initials: A
authors.lastname: Howes
authors.affiliation: Laboratory of Immunoregulation and Infection, The Francis Crick Institute, Mill Hill Laboratory, London NW7 1AA, United Kingdom;
authors.forename: Christina
authors.initials: C
authors.lastname: Taubert
authors.affiliation: Laboratory of Immunoregulation and Infection, The Francis Crick Institute, Mill Hill Laboratory, London NW7 1AA, United Kingdom;
authors.forename: Simon
authors.initials: S
authors.lastname: Blankley
authors.affiliation: London School of Hygiene and Tropical Medicine, London WC1E 7HT, United Kingdom;
authors.forename: Natasha
authors.initials: N
authors.lastname: Spink
authors.affiliation: Laboratory of Immunoregulation and Infection, The Francis Crick Institute, Mill Hill Laboratory, London NW7 1AA, United Kingdom;
authors.forename: Xuemei
authors.initials: X
authors.lastname: Wu
authors.affiliation: Laboratory of Immunoregulation and Infection, The Francis Crick Institute, Mill Hill Laboratory, London NW7 1AA, United Kingdom;
authors.forename: Christine M
authors.initials: CM
authors.lastname: Graham
authors.affiliation: Department of Research and Innovation, Neo-Life Stem Cell Biotech Inc., Sichuan Umbilical Cord Blood Bank, Chengdu, Sichuan 610036, People's Republic of China;
authors.forename: Jiawen
authors.initials: J
authors.lastname: Zhao
authors.affiliation: Life and Health Sciences Research Institute, School of Health Sciences, University of Minho, 4710-057 Braga, Portugal; Life and Health Sciences Research Institute, Biomaterials, Biodegradables and Biomimetics, Portuguese Government Associate Laboratory, 4710-057 Braga/Guimarães, Portugal;
authors.forename: Margarida
authors.initials: M
authors.lastname: Saraiva
authors.affiliation: Singapore Immunology Network, Agency for Science, Technology and Research, Singapore 138632, Singapore; and.
authors.forename: Paola
authors.identifier: 0000-0002-4749-7187
authors.initials: P
authors.lastname: Ricciardi-Castagnoli
authors.affiliation: London School of Hygiene and Tropical Medicine, London WC1E 7HT, United Kingdom;
authors.forename: Gregory J
authors.identifier: 0000-0002-7243-679X
authors.initials: GJ
authors.lastname: Bancroft
authors.affiliation: Laboratory of Immunoregulation and Infection, The Francis Crick Institute, Mill Hill Laboratory, London NW7 1AA, United Kingdom; Department of Medicine, National Heart and Lung Institute, Imperial College London, London SW3 6LY, United Kingdom Anne.OGarra@crick.ac.uk.
authors.forename: Anne
authors.identifier: 0000-0001-9845-6134
authors.initials: A
authors.lastname: O'Garra
mesh_terms: D000818:Animals; D016957:Burkholderia pseudomallei / Q000276:immunology; D016207:Cytokines / Q000096:biosynthesis* / Q000276:immunology; D007249:Inflammation / Q000276:immunology*; D007370:Interferon Type I / Q000096:biosynthesis* / Q000276:immunology; D016753:Interleukin-10 / Q000032:analysis* / Q000276:immunology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout
chemical_list: D016207:Cytokines; D007370:Interferon Type I; D008070:Lipopolysaccharides; D016753:Interleukin-10