TPL-2 Inhibits IFN-β Expression via an ERK1/2-TCF-FOS Axis in TLR4-Stimulated Macrophages
Louise Blair1, Michael J Pattison1, Probir Chakravarty2
1Immune Cell Signalling Laboratory, The Francis Crick Institute, London, United Kingdom.
Journal of Immunology (Baltimore, Md. : 1950)
|January 27, 2022
Summary
TPL-2 kinase controls gene expression in immune cells by activating ERK1/2. This pathway involves transcription factors TCF and FOS, regulating innate immunity and host defense against bacterial infection.
Area of Science:
- Immunology
- Molecular Biology
- Cell Biology
Background:
- TPL-2 kinase is crucial for innate immunity, activating ERK1/2 MAPKs in myeloid cells after Toll-like receptor (TLR) stimulation.
- Understanding TPL-2's transcriptional control mechanisms is vital for deciphering immune responses.
Purpose of the Study:
- To investigate how TPL-2 kinase controls gene transcription in TLR4-stimulated mouse macrophages.
- To elucidate the roles of transcription factors TCF and FOS in TPL-2-mediated signaling.
Main Methods:
- Transcriptomic analysis of wild-type and TCF-deficient macrophages.
- Analysis of TLR4-stimulated Fos knockout macrophages.
- Investigated ERK1/2 phosphorylation of ELK1 and TCF target gene expression.
Main Results:
- TPL-2 activation of ERK1/2 regulates genes encoding transcription factors, cytokines, chemokines, and signaling regulators.
- TCFs mediate approximately half of TPL-2's transcriptional output, partly via secondary transcription factors.
- TPL-2 signaling and TCFs are essential for maximal TLR4-induced FOS expression.
- TPL-2 regulates a significant gene fraction by controlling FOS levels.
Conclusions:
- The ERK1/2-TCF-FOS pathway is a key mechanism by which TPL-2 controls gene expression in macrophages.
- This pathway suppresses type I interferon signaling, which is critical for host resistance to intracellular bacterial infections.
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