Beta Interferon Production Is Regulated by p38 Mitogen-Activated Protein Kinase in Macrophages via both MSK1/2- and Tristetraprolin-Dependent Pathways

Victoria A. McGuire, Dalya Rosner, Olga Ananieva, Ewan A. Ross, Suzanne E. Elcombe, Shaista Naqvi, Mirjam M. W. van den Bosch, Claire E. Monk, Tamara Ruiz-Zorrilla Diez, Andrew R. Clark, J. Simon C. Arthur (Lead / Corresponding author)

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Abstract

Autocrine or paracrine signaling by the type I interferon IFNβ is essential for many of 24 the responses of macrophages to pathogen associated molecular patterns. This feedback loop contributes to pathological responses to infectious agents, and is therefore tightly regulated. We demonstrate here that macrophage expression of IFNβ is negatively regulated by mitogen- and stress-activated kinases (MSK) 1 and 2. Lipopolysaccharide- (LPS-) induced expression of IFNβ was elevated in both MSK1/2 knockout mice and macrophages. Although MSK1 and 2 promote the expression of the anti-inflammatory cytokine interleukin 10, this did not strongly contribute to the ability of MSKs to regulate IFNβ expression. Instead, MSK1 and 2 inhibit IFNβ expression via the induction of dual specificity phosphatase 1 (DUSP1), which dephosphorylates and inactivates the mitogen-activated protein kinases p38 and JNK. Prolonged LPS-induced activation of p38 and JNK, phosphorylation of downstream transcription factors, and over-expression of IFNβ mRNA and protein were similar in MSK1/2 and DUSP1 knockout macrophages. Two distinct mechanisms were implicated in the overexpression of IFNβ: first, JNK mediated activation of c-jun, which binds to the IFNβ promoter and second, p38-mediated inactivation of the mRNA-destabilizing factor tristetraprolin, which we show is able to target the IFNβ mRNA.
Original languageEnglish
Article numbere00454-16
Number of pages19
JournalMolecular and Cellular Biology
Volume37
Issue number1
Early online date17 Oct 2016
DOIs
Publication statusPublished - Jan 2017

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Tristetraprolin
Interferon-beta
p38 Mitogen-Activated Protein Kinases
Dual Specificity Phosphatase 1
Macrophages
Messenger RNA
Lipopolysaccharides
Autocrine Communication
Paracrine Communication
Interferon Type I
Mitogens
Knockout Mice
Interleukin-10
Anti-Inflammatory Agents
Transcription Factors
Phosphotransferases
Phosphorylation
Cytokines
Proteins

Cite this

McGuire, Victoria A. ; Rosner, Dalya ; Ananieva, Olga ; Ross, Ewan A. ; Elcombe, Suzanne E. ; Naqvi, Shaista ; van den Bosch, Mirjam M. W. ; Monk, Claire E. ; Ruiz-Zorrilla Diez, Tamara ; Clark, Andrew R. ; Arthur, J. Simon C. / Beta Interferon Production Is Regulated by p38 Mitogen-Activated Protein Kinase in Macrophages via both MSK1/2- and Tristetraprolin-Dependent Pathways. In: Molecular and Cellular Biology. 2017 ; Vol. 37, No. 1.
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title = "Beta Interferon Production Is Regulated by p38 Mitogen-Activated Protein Kinase in Macrophages via both MSK1/2- and Tristetraprolin-Dependent Pathways",
abstract = "Autocrine or paracrine signaling by the type I interferon IFNβ is essential for many of 24 the responses of macrophages to pathogen associated molecular patterns. This feedback loop contributes to pathological responses to infectious agents, and is therefore tightly regulated. We demonstrate here that macrophage expression of IFNβ is negatively regulated by mitogen- and stress-activated kinases (MSK) 1 and 2. Lipopolysaccharide- (LPS-) induced expression of IFNβ was elevated in both MSK1/2 knockout mice and macrophages. Although MSK1 and 2 promote the expression of the anti-inflammatory cytokine interleukin 10, this did not strongly contribute to the ability of MSKs to regulate IFNβ expression. Instead, MSK1 and 2 inhibit IFNβ expression via the induction of dual specificity phosphatase 1 (DUSP1), which dephosphorylates and inactivates the mitogen-activated protein kinases p38 and JNK. Prolonged LPS-induced activation of p38 and JNK, phosphorylation of downstream transcription factors, and over-expression of IFNβ mRNA and protein were similar in MSK1/2 and DUSP1 knockout macrophages. Two distinct mechanisms were implicated in the overexpression of IFNβ: first, JNK mediated activation of c-jun, which binds to the IFNβ promoter and second, p38-mediated inactivation of the mRNA-destabilizing factor tristetraprolin, which we show is able to target the IFNβ mRNA.",
author = "McGuire, {Victoria A.} and Dalya Rosner and Olga Ananieva and Ross, {Ewan A.} and Elcombe, {Suzanne E.} and Shaista Naqvi and {van den Bosch}, {Mirjam M. W.} and Monk, {Claire E.} and {Ruiz-Zorrilla Diez}, Tamara and Clark, {Andrew R.} and Arthur, {J. Simon C.}",
note = "This work was supported by Arthritis Research UK (JSCA and ARC), the Medical Research Council, Wellcome Trust and the pharmaceutical companies supporting the Division of Signal Transduction Therapy Unit (AstraZeneca, Boehringer-Ingelheim, GlaxoSmithKline, Merck KgaA and Janssen Pharmaceutica)(JSCA). SE was funded by a Wellcome Trust Clinical PhD studentship.",
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McGuire, VA, Rosner, D, Ananieva, O, Ross, EA, Elcombe, SE, Naqvi, S, van den Bosch, MMW, Monk, CE, Ruiz-Zorrilla Diez, T, Clark, AR & Arthur, JSC 2017, 'Beta Interferon Production Is Regulated by p38 Mitogen-Activated Protein Kinase in Macrophages via both MSK1/2- and Tristetraprolin-Dependent Pathways', Molecular and Cellular Biology, vol. 37, no. 1, e00454-16. https://doi.org/10.1128/MCB.00454-16

Beta Interferon Production Is Regulated by p38 Mitogen-Activated Protein Kinase in Macrophages via both MSK1/2- and Tristetraprolin-Dependent Pathways. / McGuire, Victoria A.; Rosner, Dalya; Ananieva, Olga; Ross, Ewan A.; Elcombe, Suzanne E.; Naqvi, Shaista; van den Bosch, Mirjam M. W.; Monk, Claire E.; Ruiz-Zorrilla Diez, Tamara; Clark, Andrew R.; Arthur, J. Simon C. (Lead / Corresponding author).

In: Molecular and Cellular Biology, Vol. 37, No. 1, e00454-16, 01.2017.

Research output: Contribution to journalArticle

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T1 - Beta Interferon Production Is Regulated by p38 Mitogen-Activated Protein Kinase in Macrophages via both MSK1/2- and Tristetraprolin-Dependent Pathways

AU - McGuire, Victoria A.

AU - Rosner, Dalya

AU - Ananieva, Olga

AU - Ross, Ewan A.

AU - Elcombe, Suzanne E.

AU - Naqvi, Shaista

AU - van den Bosch, Mirjam M. W.

AU - Monk, Claire E.

AU - Ruiz-Zorrilla Diez, Tamara

AU - Clark, Andrew R.

AU - Arthur, J. Simon C.

N1 - This work was supported by Arthritis Research UK (JSCA and ARC), the Medical Research Council, Wellcome Trust and the pharmaceutical companies supporting the Division of Signal Transduction Therapy Unit (AstraZeneca, Boehringer-Ingelheim, GlaxoSmithKline, Merck KgaA and Janssen Pharmaceutica)(JSCA). SE was funded by a Wellcome Trust Clinical PhD studentship.

PY - 2017/1

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N2 - Autocrine or paracrine signaling by the type I interferon IFNβ is essential for many of 24 the responses of macrophages to pathogen associated molecular patterns. This feedback loop contributes to pathological responses to infectious agents, and is therefore tightly regulated. We demonstrate here that macrophage expression of IFNβ is negatively regulated by mitogen- and stress-activated kinases (MSK) 1 and 2. Lipopolysaccharide- (LPS-) induced expression of IFNβ was elevated in both MSK1/2 knockout mice and macrophages. Although MSK1 and 2 promote the expression of the anti-inflammatory cytokine interleukin 10, this did not strongly contribute to the ability of MSKs to regulate IFNβ expression. Instead, MSK1 and 2 inhibit IFNβ expression via the induction of dual specificity phosphatase 1 (DUSP1), which dephosphorylates and inactivates the mitogen-activated protein kinases p38 and JNK. Prolonged LPS-induced activation of p38 and JNK, phosphorylation of downstream transcription factors, and over-expression of IFNβ mRNA and protein were similar in MSK1/2 and DUSP1 knockout macrophages. Two distinct mechanisms were implicated in the overexpression of IFNβ: first, JNK mediated activation of c-jun, which binds to the IFNβ promoter and second, p38-mediated inactivation of the mRNA-destabilizing factor tristetraprolin, which we show is able to target the IFNβ mRNA.

AB - Autocrine or paracrine signaling by the type I interferon IFNβ is essential for many of 24 the responses of macrophages to pathogen associated molecular patterns. This feedback loop contributes to pathological responses to infectious agents, and is therefore tightly regulated. We demonstrate here that macrophage expression of IFNβ is negatively regulated by mitogen- and stress-activated kinases (MSK) 1 and 2. Lipopolysaccharide- (LPS-) induced expression of IFNβ was elevated in both MSK1/2 knockout mice and macrophages. Although MSK1 and 2 promote the expression of the anti-inflammatory cytokine interleukin 10, this did not strongly contribute to the ability of MSKs to regulate IFNβ expression. Instead, MSK1 and 2 inhibit IFNβ expression via the induction of dual specificity phosphatase 1 (DUSP1), which dephosphorylates and inactivates the mitogen-activated protein kinases p38 and JNK. Prolonged LPS-induced activation of p38 and JNK, phosphorylation of downstream transcription factors, and over-expression of IFNβ mRNA and protein were similar in MSK1/2 and DUSP1 knockout macrophages. Two distinct mechanisms were implicated in the overexpression of IFNβ: first, JNK mediated activation of c-jun, which binds to the IFNβ promoter and second, p38-mediated inactivation of the mRNA-destabilizing factor tristetraprolin, which we show is able to target the IFNβ mRNA.

U2 - 10.1128/MCB.00454-16

DO - 10.1128/MCB.00454-16

M3 - Article

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JO - Molecular and Cellular Biology

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SN - 0270-7306

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