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Differential production of type I IFN determines the reciprocal levels of IL-10 and proinflammatory cytokines produced by C57BL/6 and BALB/c macrophages.

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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.
Authors: Howes, A
Taubert, C
Blankley, S
Spink, N
Wu, X
Graham, CM
Zhao, J
Saraiva, M
Ricciardi-Castagnoli, P
Bancroft, GJ
O'Garra, A
Item Type: Journal Article
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.
Issue Date: 1-Oct-2016
Date of Acceptance: 26-Jul-2016
URI: http://hdl.handle.net/10044/1/59161
DOI: https://dx.doi.org/10.4049/jimmunol.1501923
ISSN: 0022-1767
Publisher: American Association of Immunologists
Start Page: 2838
End Page: 2853
Journal / Book Title: Journal of Immunology
Volume: 197
Issue: 7
Copyright Statement: © 2016 The Authors. This is an open-access article distributed under the terms of the CC-BY 3.0 license.
Keywords: Science & Technology
Life Sciences & Biomedicine
Immunology
SIGNAL-REGULATED KINASE
TOLL-LIKE RECEPTORS
BURKHOLDERIA-PSEUDOMALLEI INFECTION
GENE-EXPRESSION
DENDRITIC CELLS
MEDIATED IL-10
INTERLEUKIN-10-DEFICIENT MICE
INFLAMMATORY FUNCTIONS
PROTEIN-KINASE
ACTIVATION
Animals
Burkholderia pseudomallei
Cytokines
Inflammation
Interferon Type I
Interleukin-10
Lipopolysaccharides
Macrophages
Mice
Mice, Inbred BALB C
Mice, Inbred C57BL
Mice, Knockout
1107 Immunology
Publication Status: Published
Appears in Collections:National Heart and Lung Institute