| First Author | Blair L | Year | 2022 |
| Journal | J Immunol | Volume | 208 |
| Issue | 4 | Pages | 941-954 |
| PubMed ID | 35082159 | Mgi Jnum | J:322244 |
| Mgi Id | MGI:7257962 | Doi | 10.4049/jimmunol.2100213 |
| Citation | Blair L, et al. (2022) TPL-2 Inhibits IFN-beta Expression via an ERK1/2-TCF-FOS Axis in TLR4-Stimulated Macrophages. J Immunol 208(4):941-954 |
| abstractText | 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. |
