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

Mol Cell Biol. 2016 Dec 19;37(1):e00454-16. doi: 10.1128/MCB.00454-16. Print 2017 Jan 1.

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, JNK-mediated 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.

Keywords: CREB; DUSP1; MSK1; MSK2; TTP; beta interferon; p38 kinases.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Communication
  • Cells, Cultured
  • Gene Expression Regulation / drug effects
  • Interferon-beta / metabolism*
  • Interleukin-10 / metabolism
  • Lipopolysaccharides / pharmacology
  • Macrophages / drug effects
  • Macrophages / immunology
  • Macrophages / metabolism*
  • Mice
  • Phosphorylation
  • Ribosomal Protein S6 Kinases, 90-kDa / metabolism*
  • Signal Transduction / drug effects
  • Tristetraprolin / metabolism*
  • p38 Mitogen-Activated Protein Kinases / metabolism*

Substances

  • IL10 protein, mouse
  • Lipopolysaccharides
  • Tristetraprolin
  • Interleukin-10
  • Interferon-beta
  • Ribosomal Protein S6 Kinases, 90-kDa
  • Rps6ka4 protein, mouse
  • mitogen and stress-activated protein kinase 1
  • p38 Mitogen-Activated Protein Kinases