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

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.

A20 upregulation during treated HIV disease is associated with intestinal epithelial cell recovery and function

“…Given our findings, we propose that the intestinal epithelial dysfunction found in untreated HIV disease is caused by high levels of type I and type II IFN activity likely mediated in part by IFNα production by plasmacytoid dendritic cells [ 41 , 57 – 59 ], IFNβ production by TLR4-stimulated macrophages [ 60 ], and IFNγ production by CD8 T cells recognizing viral particles respectively [ 45 ], that exist concurrently with low levels of IL-17A ( Fig 7 ). We show that IFNα is capable of suppressing A20 expression in IECs.…”

MAPK p38 regulates inflammatory gene expression via tristetraprolin: Doing good by stealth

“…The intimate link between MAPK p38 and TTP provides an elegant system for fine-tuning inflammatory responses, in terms of both the strength of response to challenge and the precise timing of on- and off-switches. The physiological significance of this mechanism is well illustrated by the dramatic inflammation-resistant phenotype arising from substitution of just two amino acids of endogenous TTP ( McGuire et al, 2016 , O'Neil et al, 2017 , Ross et al, 2017 , Ross et al, 2015 , Smallie et al, 2015 , Tang et al, 2017 ). At least in principle, this mechanism of control of inflammatory responses appears to be tractable as a novel therapeutic target ( Rahman et al, 2016 , Ross et al, 2017 ).…”

“…Target mRNAs are consequently destabilized, driving the off-phase of gene expression. The exact tipping point between on- and off-phases depends on the strength and duration of transcriptional activation and (possibly) the affinity of the particular mRNA for TTP ( McGuire et al, 2016 , Tang et al, 2017 ). 4.…”

“…As predicted, TTP was expressed at very low levels in genetically modified ( Zfp36aa/aa ) primary macrophages, to the extent that it was almost undetectable in some experiments. However, it functioned very efficiently as an mRNA destabilizing factor, and strongly inhibited the expression of many inflammatory mediators ( McGuire et al, 2016 , O'Neil et al, 2017 , Ross et al, 2015 , Tang et al, 2017 ). In vivo the targeted mutagenesis of the Zfp36 gene conferred strong protection in an experimental model of endotoxemia ( Ross et al, 2015 ) and complete protection in an experimental model of rheumatoid arthritis ( Ross et al, 2017 ).…”

“…The Dusp1-/- phenotype is largely explained by increased phosphorylation and inactivation of TTP, and consequent stabilization of TTP target transcripts ( Smallie et al, 2015 ). The cross-talk between DUSP1 and TTP controls the expression of several important inflammatory mediators including TNF, IL-6 (interleukin 6), IL-1β, CXCL1 (chemokine CXC motif ligand 1), CXCL2, Cyclooxygenase 2 and Interferon β ( McGuire et al, 2016 , O'Neil et al, 2017 , Smallie et al, 2015 , Tang et al, 2017 ). An implication is that agonists which enhance or prolong the expression of DUSP1 could reduce expression of these genes and exert anti-inflammatory effects by modulating the equilibrium between phosphorylated and unphosphorylated TTP.…”