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TPL-2 Inhibits IFN-β Expression via an ERK1/2-TCF-FOS Axis in TLR4-Stimulated Macrophages.

ABSTRACT: TPL-2 kinase plays an important role in innate immunity, activating ERK1/2 MAPKs in myeloid cells following TLR stimulation. We investigated how TPL-2 controls transcription in TLR4-stimulated mouse macrophages. TPL-2 activation of ERK1/2 regulated expression of genes encoding transcription factors, cytokines, chemokines, and signaling regulators. Bioinformatics analysis of gene clusters most rapidly induced by TPL-2 suggested that their transcription was mediated by the ternary complex factor (TCF) and FOS transcription factor families. Consistently, TPL-2 induced ERK1/2 phosphorylation of the ELK1 TCF and the expression of TCF target genes. Furthermore, transcriptomic analysis of TCF-deficient macrophages demonstrated that TCFs mediate approximately half of the transcriptional output of TPL-2 signaling, partially via induced expression of secondary transcription factors. TPL-2 signaling and TCFs were required for maximal TLR4-induced FOS expression. Comparative analysis of the transcriptome of TLR4-stimulated Fos ^-/- macrophages indicated that TPL-2 regulated a significant fraction of genes by controlling FOS expression levels. A key function of this ERK1/2-TCF-FOS pathway was to mediate TPL-2 suppression of type I IFN signaling, which is essential for host resistance against intracellular bacterial infection.

SUBMITTER: Blair L

PROVIDER: S-EPMC9012084 | biostudies-literature |

REPOSITORIES: biostudies-literature

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TPL-2 inhibits interferon-beta expression via an ERK1/2-TCF-FOS axis in TLR4-stimulated macrophages

Project description:Studies in mice have indicated that TPL2 kinase plays important roles in immune responses to pathogens and in various models of inflammatory disease. We set out to determine how TPL2 (Map3k8) regulates transcription using an in vitro system of LPS-stimulated primary macrophages. TPL2 regulated genes are involved in a number of different processes including inflammation as well as reproduction, cell cycle and signal transduction. Differentially expressed genes were used in a K means analysis, grouping based on expression profile, which identified 12 different expression profiles. There was a strong correlation between rapidly-induced genes regulated by TPL2 kinase activity and their expression in cells treated with the MKK1/2 inhibitor (PD032590)1 or from cells where phosphorylation of P105 by IKK2 is blocked. Cluster 1 genes were found to be enriched for TCF family members. TPL2 was shown to regulate ELK1 phosphorylation and known TCF targets genes such as Egr1. TPL2 is known to regulate transcription of multiple cytokines and chemokines including IFNb. Like Map3k8[D270A] macrophages, expression of Ifnb1 was increased in Elk1-/-Elk4-/- macrophages compared to WT macrophages following LPS stimulation. In fact, this increase was also seen in MKK1/2 inhibitor treated macrophages. Expression of Fos was decreased in both Map3k8[D270A] and Elk1-/-Elk4-/- macrophages. Macrophages generated from mice with myeloid-specific deletion of Fos also had elevated levels of Ifnb1 compared to controls. Similar results were obtained following activation of TLR1/2, TLR9 and TNF-R in macrophages. Furthermore, LPS or TNF stimulation of MEFs lacking Elk1, Elk3 and Elk4 had reduced FOS protein levels and increased Ifnb1 mRNA suggesting a general role for ERK1/2 > TCF pathway regulating Ifnb1 levels through Fos expression.

2021-10-26 | GSE178921 | GEO

TPL-2 inhibits interferon-beta expression via an ERK1/2-TCF-FOS axis in TLR4-stimulated macrophages

Project description:TPL-2 inhibits interferon-beta expression via an ERK1/2-TCF-FOS axis in TLR4-stimulated macrophages

| PRJNA741502 | ENA

The TPL-2 – ERK1/2 signalling pathway inhibits interferon beta expression in macrophages via TCF-dependent Fos transcription

2020-06-22 | GSE116220 | GEO

NF-?B1 inhibits TLR-induced IFN-? production in macrophages through TPL-2-dependent ERK activation.

Project description:Although NF-?B1 p50/p105 has critical roles in immunity, the mechanism by which NF-?B1 regulates inflammatory responses is unclear. In this study, we analyzed the gene expression profile of LPS-stimulated Nfkb1(-/-) macrophages that lack both p50 and p105. Deficiency of p50/p105 selectively increased the expression of IFN-responsive genes, which correlated with increased IFN-? expression and STAT1 phosphorylation. IFN Ab-blocking experiments indicated that increased STAT1 phosphorylation and expression of IFN-responsive genes observed in the absence of p50/p105 depended upon autocrine IFN-? production. Markedly higher serum levels of IFN-? were observed in Nfkb1(-/-) mice than in wild-type mice following LPS injection, demonstrating that Nfkb1 inhibits IFN-? production under physiological conditions. TPL-2, a mitogen-activated protein kinase kinase kinase stabilized by association with the C-terminal ankyrin repeat domain of p105, negatively regulates LPS-induced IFN-? production by macrophages via activation of ERK MAPK. Retroviral expression of TPL-2 in Nfkb1(-/-) macrophages, which are deficient in endogenous TPL-2, reduced LPS-induced IFN-? secretion. Expression of the C-terminal ankyrin repeat domain of p105 in Nfkb1(-/-) macrophages, which rescued LPS activation of ERK, also inhibited IFN-? expression. These data indicate that p50/p105 negatively regulates LPS-induced IFN signaling in macrophages by stabilizing TPL-2, thereby facilitating activation of ERK.

| S-EPMC3070925 | biostudies-literature

The TPL-2 – ERK1/2 signalling pathway inhibits interferon beta expression in macrophages via TCF-dependent Fos transcription

Project description:The TPL-2 – ERK1/2 signalling pathway inhibits interferon beta expression in macrophages via TCF-dependent Fos transcription

| PRJNA477798 | ENA

Autocrine IFN-I inhibits isocitrate dehydrogenase in the TCA cycle of LPS-stimulated macrophages.

Project description:Macrophage activation in response to LPS is coupled to profound metabolic changes, typified by accumulation of the TCA cycle intermediates citrate, itaconate, and succinate. We have identified that endogenous type I IFN controls the cellular citrate/α-ketoglutarate ratio and inhibits expression and activity of isocitrate dehydrogenase (IDH); and, via 13C-labeling studies, demonstrated that autocrine type I IFN controls carbon flow through IDH in LPS-activated macrophages. We also found that type I IFN-driven IL-10 contributes to inhibition of IDH activity and itaconate synthesis in LPS-stimulated macrophages. Our findings have identified the autocrine type I IFN pathway as being responsible for the inhibition of IDH in LPS-stimulated macrophages.

| S-EPMC6763227 | biostudies-literature

TPL-2-ERK1/2 signaling promotes host resistance against intracellular bacterial infection by negative regulation of type I IFN production.

Project description:Tuberculosis, caused by Mycobacterium tuberculosis, remains a leading cause of mortality and morbidity worldwide, causing ? 1.4 million deaths per year. Key immune components for host protection during tuberculosis include the cytokines IL-12, IL-1, and TNF-?, as well as IFN-? and CD4(+) Th1 cells. However, immune factors determining whether individuals control infection or progress to active tuberculosis are incompletely understood. Excess amounts of type I IFN have been linked to exacerbated disease during tuberculosis in mouse models and to active disease in patients, suggesting tight regulation of this family of cytokines is critical to host resistance. In addition, the immunosuppressive cytokine IL-10 is known to inhibit the immune response to M. tuberculosis in murine models through the negative regulation of key proinflammatory cytokines and the subsequent Th1 response. We show in this study, using a combination of transcriptomic analysis, genetics, and pharmacological inhibitors, that the TPL-2-ERK1/2 signaling pathway is important in mediating host resistance to tuberculosis through negative regulation of type I IFN production. The TPL-2-ERK1/2 signaling pathway regulated production by macrophages of several cytokines important in the immune response to M. tuberculosis as well as regulating induction of a large number of additional genes, many in a type I IFN-dependent manner. In the absence of TPL-2 in vivo, excess type I IFN promoted IL-10 production and exacerbated disease. These findings describe an important regulatory mechanism for controlling tuberculosis and reveal mechanisms by which type I IFN may promote susceptibility to this important disease.

| S-EPMC3796877 | biostudies-literature

Histone hyperacetylation mediates enhanced IL-1? production in LPS/IFN-?-stimulated macrophages.

Project description:Under the condition of lipopolysaccharide (LPS)/interferon (IFN)-? activation, macrophage metabolism is converted from oxidative phosphorylation to glycolysis. In the present work, we analysed whether glycolysis could affect interleukin (IL)-1? expression through altering histone acetylation levels in mouse bone marrow-derived macrophages. Immunocytochemistry and Western blot analysis are used to characterize histone acetylation in macrophages stimulated by LPS/IFN-?. Real-time polymerase chain reaction and enzyme-linked immunosorbent assay were used to determine IL-1? production. The metabolism of macrophages was monitored in real-time by the Seahorse test. Our results showed that glycolytic metabolism could enhance histone acetylation and promote IL-1? production in LPS/IFN-?-activated macrophages. Moreover, increased production of IL-1? by glycolysis was mediated through enhanced H3K9 acetylation. Importantly, it was found that a high dose of histone deacetylase inhibitor could also significantly increase the expression of IL-1? in the absence of glycolytic metabolism. In conclusion, this study demonstrates that glycolytic metabolism could regulate IL-1? expression by increasing histone acetylation levels in LPS/IFN-?-stimulated macrophages.

| S-EPMC7218666 | biostudies-literature

IFN-? and TNF-?-induced GBP-1 inhibits epithelial cell proliferation through suppression of ?-catenin/TCF signaling.

Project description:Proinflammatory cytokines induce guanylate-binding protein 1 (GBP-1) protein expression in intestinal epithelial tissues. GBP-1 has been described as influencing a number of cellular processes important for epithelial homeostasis, including cell proliferation. However, many questions remain as to the role of GBP-1 in intestinal mucosal homeostasis. We therefore sought to investigate the function of proinflammatory cytokine-induced GBP-1 during intestinal epithelial cell proliferation. Through the use of complementary GBP-1 overexpression and small interfering RNA-mediated knockdown studies, we now show that GBP-1 acts to inhibit pro-mitogenic ?-catenin/T cell factor (TCF) signaling. Interestingly, proinflammatory cytokine-induced GBP-1 was found to be a potent suppressor of ?-catenin protein levels and ?-catenin serine 552 phosphorylation. Neither glycogen synthase kinase 3? nor proteasomal inhibition alleviated GBP-1-mediated suppression of cell proliferation or ?-catenin/TCF signaling, indicating a non-canonical mechanism of ?-catenin inhibition. Together, these data show that cytokine-induced GBP-1 retards cell proliferation by forming a negative feedback loop that suppresses ?-catenin/TCF signaling.

| S-EPMC3481006 | biostudies-literature

Eps8 protein facilitates phagocytosis by increasing TLR4-MyD88 protein interaction in lipopolysaccharide-stimulated macrophages.

Project description:Toll-like receptors (TLRs) are crucial in macrophage phagocytosis, which is pivotal in host innate immune response. However, the detailed mechanism is not fully defined. Here, we demonstrated that the induction of Src and Eps8 in LPS-treated macrophages was TLR4- and MyD88-dependent, and their attenuation reduced LPS-promoted phagocytosis. Confocal microscopy indicated the colocalization of Eps8 and TLR4 in the cytosol and at the phagosome. Consistently, both Eps8 and TLR4 were present in the same immunocomplex regardless of LPS stimulation. Inhibition of this complex formation by eps8 siRNA or overexpression of pleckstrin homology domain-truncated Eps8 (i.e. 261-p97(Eps8)) decreased LPS-induced TLR4-MyD88 interaction and the following activation of Src, focal adhesion kinase, and p38 MAPK. Importantly, attenuation of Eps8 impaired the bacterium-killing ability of macrophages. Thus, Eps8 is a key regulator of the LPS-stimulated TLR4-MyD88 interaction and contributes to macrophage phagocytosis.

| S-EPMC3365777 | biostudies-literature

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