MAPK15 Prevents IFNB1 Expression by Suppressing Oxidative Stress-Dependent Activation of the JNK-JUN Pathway

TL;DR

This study shows that MAPK15 prevents IFNB1 expression by reducing oxidative stress and JNK-JUN pathway activation, offering a new therapeutic target for immune-related diseases.

Contribution

The study identifies MAPK15 as a novel regulator of IFNB1 expression through suppression of oxidative stress and JNK-JUN pathway activation.

Findings

MAPK15 downregulation increases IFNB1 and interferon-stimulated gene expression and secretion.

MAPK15 downregulation activates JUN via the JNK pathway, which is mediated by oxidative stress.

Antioxidant treatment reverses JUN activation and IFNB1 expression caused by MAPK15 downregulation.

Abstract

Human type I interferons are crucial regulators of immune responses, essential for controlling infections and activating immune cells. Among them, Interferon Beta (IFNB1) plays a key role in inflammation, and its dysregulation is linked to various diseases, driving efforts to understand the molecular events governing its expression. Here, we identified Mitogen-Activated Protein Kinase 15 (MAPK15) as a novel regulator of IFNB1. Using luciferase reporter assays, gene expression analysis and Enzyme-Linked Immunosorbent Assay (ELISA), we found that MAPK15 downregulation enhanced IFNB1 and Interferon-Stimulated Genes expression and increased IFNB1 secretion. To unveil the underlying mechanisms, we investigated the transcription factors acting on the IFNB1 promoter, revealing that MAPK15 downregulation induced JUN activation. Importantly, pharmacological inhibition of c-Jun N-terminal Kinases (JNKs) supported a key role for this enzyme in JUN activation and consequent IFNB1 expression. Ultimately, by using the antioxidant N-acetylcysteine ethyl ester (NACET), we demonstrated that oxidative stress, induced by MAPK15 downregulation, was responsible for JUN activation and IFNB1 expression. Overall, our findings unveil a novel mechanism by which MAPK15 modulates IFNB1 expression, positioning this kinase as a pivotal regulator of this gene. This insight opens promising avenues for therapeutic intervention, as targeting MAPK15 activity could offer a strategy to rebalance cytokine expression in chronic inflammatory diseases characterized by immune dysregulation.

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