Signaling pathways underlying TGF-β mediated suppression of IL-12A gene expression in monocytes.

Transforming growth factor-β (TGF-β) is a pleiotropic cytokine essential for multiple biological processes, including the regulation of inflammatory and immune responses. One of the important functions of TGF-β is the suppression of the proinflammatory cytokine interleukin-12 (IL-12), which is crucial for mounting an anti-tumorigenic response. Although the regulation of the IL-12p40 subunit (encoded by the IL-12B gene) of IL-12 has been extensively investigated, the knowledge of IL-12p35 (encoded by IL-12A gene) subunit regulation is relatively limited. This study investigates the molecular regulation of IL-12A by TGF-β-activated signaling pathways in THP-1 monocytes. Our study identifies a complex regulation of IL-12A gene expression by TGF-β, which involves multiple cellular signaling pathways, such as Smad2/3, NF-κB, p38 and JNK1/2. Pharmacological inhibition of NF-κB signaling decreased IL-12A expression, while blocking the Smad2/3 signaling pathway by overexpression of Smad7 and inhibiting JNK1/2 signaling with a pharmacological inhibitor, SP600125, increased its expression. The elucidated signaling pathways that regulate IL-12A gene expression potentially provide new therapeutic targets to increase IL-12 levels in the tumor microenvironment. Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.

Citation

Tetiana Hourani, Mahtab Eivazitork, Thivya Balendran, Kevin Mc Lee, John A Hamilton, Hong-Jian Zhu, Josephine Iaria, Andrew P Morokoff, Rodney B Luwor, Adrian A Achuthan. Signaling pathways underlying TGF-β mediated suppression of IL-12A gene expression in monocytes. Molecular immunology. 2024 Feb;166:101-109

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PMID: 38278031

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