Beta interferon production is regulated by P38 mitogen-activated protein kinase in macrophages via both MSK1/2-and tristetraprolin-dependent pathways


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.

Publication DOI:
Divisions: College of Health & Life Sciences
College of Health & Life Sciences > School of Biosciences
Funding Information: We thank Nathanael Gray (Dana-Farber Cancer Institute, Harvard) for the JNK inhibitor. This work was supported by Arthritis Research UK (J.S.C.A. and A.R.C.), the Medical Research Council, Wellcome Trust, and the pharmaceutical companies supporting the Di
Additional Information: Copyright © 2016 McGuire et al. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license.
Uncontrolled Keywords: Beta interferon,DUSP1,MSK1,MSK2,P38 kinases,TTP,Molecular Biology,Cell Biology
Publication ISSN: 1098-5549
Last Modified: 09 May 2024 07:12
Date Deposited: 30 Aug 2019 09:49
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Related URLs: http://www.scop ... tnerID=8YFLogxK (Scopus URL)
PURE Output Type: Article
Published Date: 2017-01-01
Published Online Date: 2016-12-19
Accepted Date: 2016-10-07
Authors: McGuire, Victoria A.
Rosner, Dalya
Ananieva, Olga
Ross, Ewan A. (ORCID Profile 0000-0001-5733-9361)
Elcombe, Suzanne E.
Naqvi, Shaista
Bosch, Mirjam M.W.van den
Monk, Claire E.
Diez, Tamara Ruiz Zorrilla
Clark, Andrew R.
Arthur, J. Simon C.



Version: Published Version

License: Creative Commons Attribution

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