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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McGuire, V. A., Rosner, D., Ananieva, O., Ross, E. A., Elcombe, S. E., Naqvi, S., van den Bosch, M. M. W., Monk, C. E., Ruiz-Zorrilla Diez, T., Clark, A. R., & Arthur, J. S. C. (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, 37(1), [e00454-16]. https://doi.org/10.1128/MCB.00454-16