Differential regulation of Toll-like receptor 4-induced interleukin-10 induction in macrophages and B cells reveals a role for p90 ribosomal S6 kinases

Ruhcha V. Sutavani, Iain R. Phair, Rebecca Barker, Alison McFarlane, Natalia Shpiro, Stuart Lang, Andrew Woodland, J. Simon C. Arthur (Lead / Corresponding author)

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Abstract

Increasing evidence has linked dysregulated IL-10 production by IL-10+ve B cells to autoimmunity, highlighting the importance of improving the understanding of the regulation of IL-10 production in these cells. In both B cells and myeloid cells, IL-10 can be produced in response to Toll-like receptor (TLR) agonists. In macrophages, previous studies have established that mitogen- and stress-activated protein kinases (MSKs) regulate IL-10 production via the phosphorylation of cAMP response element-binding (CREB) protein on the IL-10 promoter. We found here that although MSKs are activated in peritoneal B cells in response to TLR4 agonists, neither MSKs nor CREB are required for IL-10 production in these cells. Using a combination of chemical inhibitors and knockout mice, we found that IL-10 induction in B cells was regulated by an ERK1/2- and p90 ribosomal S6 kinases (RSKs)-dependent mechanism, unlike in macrophages in which RSK was not required. This observation highlights fundamental differences in the signaling controlling IL-10 production in B cells and macrophages, even though these two cell types respond to a common TLR stimulus.

Original languageEnglish
Pages (from-to)2302-2317
Number of pages16
JournalJournal of Biological Chemistry
Volume293
Issue number7
Early online date11 Dec 2017
DOIs
Publication statusPublished - 16 Feb 2018

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90-kDa Ribosomal Protein S6 Kinases
Toll-Like Receptor 4
Macrophages
Interleukin-10
B-Lymphocytes
Cells
Heat-Shock Proteins
Mitogen-Activated Protein Kinases
Mitogens
Protein Kinases
Toll-Like Receptors
Ribosomal Protein S6 Kinases
Cyclic AMP Response Element-Binding Protein
Phosphorylation
Response Elements
Myeloid Cells
Autoimmunity
Knockout Mice

Keywords

  • Journal article
  • cAMP response element-binding protein (CREB)
  • Extracellular-signal-regulated kinase (ERK)
  • p38 MAPK
  • RSK
  • Toll-like receptor 4 (TLR4)
  • Interleukin 10
  • MSK1

Cite this

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title = "Differential regulation of Toll-like receptor 4-induced interleukin-10 induction in macrophages and B cells reveals a role for p90 ribosomal S6 kinases",
abstract = "Increasing evidence has linked dysregulated IL-10 production by IL-10+ve B cells to autoimmunity, highlighting the importance of improving the understanding of the regulation of IL-10 production in these cells. In both B cells and myeloid cells, IL-10 can be produced in response to Toll-like receptor (TLR) agonists. In macrophages, previous studies have established that mitogen- and stress-activated protein kinases (MSKs) regulate IL-10 production via the phosphorylation of cAMP response element-binding (CREB) protein on the IL-10 promoter. We found here that although MSKs are activated in peritoneal B cells in response to TLR4 agonists, neither MSKs nor CREB are required for IL-10 production in these cells. Using a combination of chemical inhibitors and knockout mice, we found that IL-10 induction in B cells was regulated by an ERK1/2- and p90 ribosomal S6 kinases (RSKs)-dependent mechanism, unlike in macrophages in which RSK was not required. This observation highlights fundamental differences in the signaling controlling IL-10 production in B cells and macrophages, even though these two cell types respond to a common TLR stimulus.",
keywords = "Journal article, cAMP response element-binding protein (CREB) , Extracellular-signal-regulated kinase (ERK) , p38 MAPK , RSK , Toll-like receptor 4 (TLR4) , Interleukin 10 , MSK1",
author = "Sutavani, {Ruhcha V.} and Phair, {Iain R.} and Rebecca Barker and Alison McFarlane and Natalia Shpiro and Stuart Lang and Andrew Woodland and Arthur, {J. Simon C.}",
note = "This work was funded by the Medical Research Council and Arthritis Research UK.",
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TY - JOUR

T1 - Differential regulation of Toll-like receptor 4-induced interleukin-10 induction in macrophages and B cells reveals a role for p90 ribosomal S6 kinases

AU - Sutavani, Ruhcha V.

AU - Phair, Iain R.

AU - Barker, Rebecca

AU - McFarlane, Alison

AU - Shpiro, Natalia

AU - Lang, Stuart

AU - Woodland, Andrew

AU - Arthur, J. Simon C.

N1 - This work was funded by the Medical Research Council and Arthritis Research UK.

PY - 2018/2/16

Y1 - 2018/2/16

N2 - Increasing evidence has linked dysregulated IL-10 production by IL-10+ve B cells to autoimmunity, highlighting the importance of improving the understanding of the regulation of IL-10 production in these cells. In both B cells and myeloid cells, IL-10 can be produced in response to Toll-like receptor (TLR) agonists. In macrophages, previous studies have established that mitogen- and stress-activated protein kinases (MSKs) regulate IL-10 production via the phosphorylation of cAMP response element-binding (CREB) protein on the IL-10 promoter. We found here that although MSKs are activated in peritoneal B cells in response to TLR4 agonists, neither MSKs nor CREB are required for IL-10 production in these cells. Using a combination of chemical inhibitors and knockout mice, we found that IL-10 induction in B cells was regulated by an ERK1/2- and p90 ribosomal S6 kinases (RSKs)-dependent mechanism, unlike in macrophages in which RSK was not required. This observation highlights fundamental differences in the signaling controlling IL-10 production in B cells and macrophages, even though these two cell types respond to a common TLR stimulus.

AB - Increasing evidence has linked dysregulated IL-10 production by IL-10+ve B cells to autoimmunity, highlighting the importance of improving the understanding of the regulation of IL-10 production in these cells. In both B cells and myeloid cells, IL-10 can be produced in response to Toll-like receptor (TLR) agonists. In macrophages, previous studies have established that mitogen- and stress-activated protein kinases (MSKs) regulate IL-10 production via the phosphorylation of cAMP response element-binding (CREB) protein on the IL-10 promoter. We found here that although MSKs are activated in peritoneal B cells in response to TLR4 agonists, neither MSKs nor CREB are required for IL-10 production in these cells. Using a combination of chemical inhibitors and knockout mice, we found that IL-10 induction in B cells was regulated by an ERK1/2- and p90 ribosomal S6 kinases (RSKs)-dependent mechanism, unlike in macrophages in which RSK was not required. This observation highlights fundamental differences in the signaling controlling IL-10 production in B cells and macrophages, even though these two cell types respond to a common TLR stimulus.

KW - Journal article

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KW - Extracellular-signal-regulated kinase (ERK)

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KW - RSK

KW - Toll-like receptor 4 (TLR4)

KW - Interleukin 10

KW - MSK1

U2 - 10.1074/jbc.M117.805424

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