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*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Autocrine or paracrine signaling by beta interferon (IFN-β) is essential for many of 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 IFN-β is negatively regulated by mitogen- and stress-activated kinases 1 and 2 (MSK1/2). Lipopolysaccharide (LPS)-induced expression of IFN-β was elevated in both MSK1/2 knockout mice and macrophages. Although MSK1 and -2 promote the expression of the anti-inflammatory cytokine interleukin 10, it did not strongly contribute to the ability of MSKs to regulate IFN-β expression. Instead, MSK1 and -2 inhibit IFN-β expression via the induction of dual-specificity phosphatase 1 (DUSP1), which dephosphorylates and inactivates the mitogen-activated protein kinases p38 and Jun N-terminal protein kinase (JNK). Prolonged LPS-induced activation of p38 and JNK, phosphorylation of downstream transcription factors, and overexpression of IFN-β mRNA and protein were similar in MSK1/2 and DUSP1 knockout macrophages. Two distinct mechanisms were implicated in the overexpression of IFN-β: first, JNKmediated activation of c-jun, which binds to the IFN-β promoter, and second, p38-mediated inactivation of the mRNA-destabilizing factor tristetraprolin, which we show is able to target the IFN-β mRNA.

Original languageEnglish
Article numbere00454-16
JournalMolecular and Cellular Biology
Volume37
Issue number1
Early online date19 Dec 2016
DOIs
Publication statusPublished - 1 Jan 2017

Bibliographical note

Copyright © 2016 McGuire et al.
This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license.

Keywords

  • Beta interferon
  • DUSP1
  • MSK1
  • MSK2
  • P38 kinases
  • TTP

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