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
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
Full Text Link:
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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