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Differential Production of Type I IFN

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Differential Production of Type I IFN Differential Production of Type I IFN Determines the Reciprocal Levels of IL-10 and Proinflammatory Cytokines Produced by C57BL/6 and BALB/c Macrophages This information is current as of September 29, 2021. Ashleigh Howes, Christina Taubert, Simon Blankley, Natasha Spink, Xuemei Wu, Christine M. Graham, Jiawen Zhao, Margarida Saraiva, Paola Ricciardi-Castagnoli, Gregory J. Bancroft and Anne O'Garra J Immunol 2016; 197:2838-2853; Prepublished online 22 Downloaded from August 2016; doi: 10.4049/jimmunol.1501923 http://www.jimmunol.org/content/197/7/2838 http://www.jimmunol.org/ Supplementary http://www.jimmunol.org/content/suppl/2016/08/21/jimmunol.150192 Material 3.DCSupplemental References This article cites 51 articles, 27 of which you can access for free at: http://www.jimmunol.org/content/197/7/2838.full#ref-list-1 by guest on September 29, 2021 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2016 The Authors All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Differential Production of Type I IFN Determines the Reciprocal Levels of IL-10 and Proinflammatory Cytokines Produced by C57BL/6 and BALB/c Macrophages Ashleigh Howes,*,1 Christina Taubert,*,1 Simon Blankley,* Natasha Spink,† Xuemei Wu,* Christine M. Graham,* Jiawen Zhao,‡ Margarida Saraiva,x,{ Paola Ricciardi-Castagnoli,‖ Gregory J. Bancroft,† and Anne O’Garra*,# Pattern recognition receptors detect microbial products and induce cytokines, which shape the immunological response. IL-12, TNF-a, and IL-1b 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 Downloaded from 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-a,andIL-1b, 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 http://www.jimmunol.org/ factor 3 activation. Furthermore, type I IFN contributed to differential IL-1b 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. The Journal of Immunology, 2016, 197: 2838–2853. roinflammatory immune responses are critical in the de- feedback regulator in the immune system. IL-10 can be produced fense against pathogens; however, excessive inflammation by several cell types within the immune system, including PRR- P has the potential to cause damage to the host. Thus, immu- stimulated macrophages (6), to which IL-10 can signal back in an by guest on September 29, 2021 noregulatory pathways controlling inflammatory cytokine production autocrine manner and inhibit the production of proinflammatory are critical for ensuring an effective but balanced immune response cytokines via a STAT3-dependent mechanism (7–9). (1). Pattern recognition receptor (PRR)–activated macrophages are an Type I IFNs constitute a group of cytokines including IFN-b and important early source of proinflammatory cytokines such as IL-12, multiple IFN-a proteins (10). Studies of the functions of type I TNF-a,andIL-1b, and their production is modulated by a complex IFN have revealed complex immunoregulatory roles for these array of direct and indirect regulatory mechanisms (1, 2). cytokines. For example, type I IFN has been shown to promote A central negative regulator of inflammatory responses is the the production of IL-10 from murine macrophages (11), hu- immunosuppressive cytokine IL-10 (3). The spontaneous onset of man monocytes (12), and human dendritic cells (13), although colitis in response to commensal gut flora in IL-10–deficient mice the mechanisms by which this occurs are not fully understood. In (4) and enhanced susceptibility of IL-10–deficient mice to septic the context of proinflammatory cytokine production, the effects of shock (5) demonstrate the importance of IL-10 as a negative type I IFN are diverse. Mechanisms whereby type I IFN regulates *Laboratory of Immunoregulation and Infection, The Francis Crick Institute, Mill Research Council Grant 294682-TB-PATH (Crick 10127). A.H. was additionally Hill Laboratory, London NW7 1AA, United Kingdom; †London School of Hygiene funded by a U.K. Medical Research Council Centenary Award. M.S. was funded and Tropical Medicine, London WC1E 7HT, United Kingdom; ‡Department of Re- by Fundac¸a˜o para a Cieˆncia e Tecnologia, Portugal Grant FCT-ANR/BIM-MEC/ search and Innovation, Neo-Life Stem Cell Biotech Inc., Sichuan Umbilical Cord 0007/2013. M.S. is an associate Fundac¸a˜o para a Cieˆncia e Tecnologia, Portugal Blood Bank, Chengdu, Sichuan 610036, People’s Republic of China; xLife and investigator. Health Sciences Research Institute, School of Health Sciences, University of Minho, { The microarray data presented in this article have been submitted to the Gene 4710-057 Braga, Portugal; Life and Health Sciences Research Institute, Biomate- Expression Omnibus Database (http://www.ncbi.nlm.nih.gov/geo/) under accession rials, Biodegradables and Biomimetics, Portuguese Government Associate Labora- ‖ number GSE79809. tory, 4710-057 Braga/Guimara˜es, Portugal; Singapore Immunology Network, Agency for Science, Technology and Research, Singapore 138632, Singapore; and Address correspondence and reprint requests to Dr. Anne O’Garra, The Francis Crick #Department of Medicine, National Heart and Lung Institute, Imperial College London, Institute, Mill Hill Laboratory, The Ridgeway, Mill Hill, London, NW7 1AA, U.K. London SW3 6LY, United Kingdom E-mail address: [email protected] 1A.H. and C.T. contributed equally to this work. The online version of this article contains supplemental material. ORCIDs: 0000-0002-4749-7187 (P.R.-C.); 0000-0002-7243-679X (G.J.B.); 0000- Abbreviations used in this article: BMDM, bone marrow–derived macrophage; IPA, 0001-9845-6134 (A.O.). Ingenuity Pathway Analysis; IRF, IFN regulatory factor; PRR, pattern recognition receptor; qRT-PCR, quantitative real-time PCR; RU, relative unit; WT, wild-type. Received for publication August 28, 2015. Accepted for publication July 26, 2016. This is an open-access article distributed under the terms of the CC-BY 3.0 Unported This work was supported by The Francis Crick Institute, which receives its core license. funding from Cancer Research UK (FC001126), the U.K. Medical Research Council (FC001126), and the Wellcome Trust (FC001126) since April 1, 2015 and before that Ó by U.K. Medical Research Council Grant MRC U117565642 and also by European Copyright 2016 The Authors 0022-1767/16 www.jimmunol.org/cgi/doi/10.4049/jimmunol.1501923 The Journal of Immunology 2839 distinct proinflammatory cytokines are as yet unclear (14–19). The Ifnar12/2 breeders originated from B&K Universal (Hull, U.K.), and 2/2 2/2 role of type I IFN in vivo in the context of infection and inflam- C57BL/6 Tccr (referred to as Il27ra in text) breeders were provided mation is complex (20). Type I IFN has been shown in different by Genentech (South San Francisco, CA). All mice used were females be- tween 8 and 16 wk of age. settings to contribute to control of the pathogen or, conversely, may regulate or exacerbate inflammatory pathologies (20). Generation and stimulation of bone marrow–derived C57BL/6 and BALB/c mice differ significantly in their immune macrophages responses, giving rise to distinct outcomes of infection, and they Bone marrow–derived macrophages (BMDMs) were generated as previ- have provided robust models for studying susceptibility or resis- ously described (33). On day 6, adherent cells were harvested and seeded tance to various pathogens (21–23). Burkholderia pseudomallei is in 48-well tissue culture plates at 0.5 3 106 cells/well and rested for 18–20 h a Gram-negative bacterium and the causative agent of melioidosis, prior to stimulation. Cells were stimulated, unless otherwise stated, with a major cause of sepsis and mortality in endemic regions of 10 ng/ml Salmonella minnesota LPS (Alexis Biochemicals), 200 ng/ml Pam3CSK4 (InvivoGen), or heat-killed (to avoid heavy Containment Level Southeast Asia and Northern Australia and is increasingly being 3work)B. pseudomallei 576 at a ratio of 5–500 B. pseudomallei to 1 reported across the tropics. There is no available vaccine, antibi- BMDM. Data were verified to be similar at the cytokine protein and mRNA otic treatment is prolonged and not always effective, and mortality levels using live B. pseudomallei 576 (data not shown).
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