TPL-2 Inhibits IFN-ß Expression via an ERK1/2-TCF-FOS Axis in TLR4-Stimulated Macrophages.
J Immunol
; 208(4): 941-954, 2022 02 15.
Article
en En
| MEDLINE
| ID: mdl-35082159
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.
Texto completo:
1
Colección:
01-internacional
Asunto principal:
Transducción de Señal
/
Proteínas Proto-Oncogénicas
/
Interferón beta
/
Quinasas Quinasa Quinasa PAM
/
Receptor Toll-Like 4
/
Macrófagos
Límite:
Animals
Idioma:
En
Revista:
J Immunol
Año:
2022
Tipo del documento:
Article
País de afiliación:
Reino Unido