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

Blair, Louise, Pattison, Michael J, Chakravarty, Probir, Papoutsopoulou, Stamatia ORCID: 0000-0001-6665-8508, Bakiri, Latifa, Wagner, Erwin F, Smale, Stephen and Ley, Steven C (2022) TPL-2 Inhibits IFN-β Expression via an ERK1/2-TCF-FOS Axis in TLR4-Stimulated Macrophages. JOURNAL OF IMMUNOLOGY, 208 (4). pp. 941-954.

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Official URL: http://dx.doi.org/10.4049/jimmunol.2100213

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 <i>Fos</i> <sup>-/-</sup> 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.

Item Type:	Article
Uncontrolled Keywords:	Macrophages, Animals, Mice, Knockout, Mice, MAP Kinase Kinase Kinases, Mitogen-Activated Protein Kinase 1, Mitogen-Activated Protein Kinase 3, Lipopolysaccharides, Proto-Oncogene Proteins c-fos, Interferon-beta, Proto-Oncogene Proteins, Signal Transduction, Macrophage Activation, Gene Expression Regulation, Toll-Like Receptor 4, TCF Transcription Factors
Divisions:	Faculty of Health and Life Sciences Faculty of Health and Life Sciences > Institute of Infection, Veterinary and Ecological Sciences
Depositing User:	Symplectic Admin
Date Deposited:	25 Jan 2023 11:00
Last Modified:	17 Oct 2023 07:11
DOI:	10.4049/jimmunol.2100213
Open Access URL:	https://doi.org/10.4049/jimmunol.2100213
Related URLs:	Author Publisher
URI:	https://livrepository.liverpool.ac.uk/id/eprint/3167872