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

• Published in: Molecular immunology Vol. 166; pp. 101 - 109
• Main Authors: Hourani, Tetiana, Eivazitork, Mahtab, Balendran, Thivya, MC. Lee, Kevin, Hamilton, John A., Zhu, Hong-Jian, Iaria, Josephine, Morokoff, Andrew P., Luwor, Rodney B., Achuthan, Adrian A.
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.02.2024
• Subjects: Glioblastoma; IL-12; Inflammation; Monocytes; Signaling; TGF-β; Signaling; TGF-β; Monocytes; Inflammation; IL-12; Glioblastoma
• ISSN: 0161-5890; 1872-9142
• DOI: 10.1016/j.molimm.2024.01.008

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. [Display omitted] •TGF-β downregulates IL-12A gene expression in monocytes.•Inhibition of TGF-β-induced activity of Smad2/3 leads to upregulation of IL-12A gene.•Pharmacological inhibition of JNK1/2 pathway leads to upregulation of IL-12A gene.