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 cruci...
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Published in | Molecular immunology Vol. 166; pp. 101 - 109 |
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Main Authors | , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
England
Elsevier Ltd
01.02.2024
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Subjects | |
Online Access | Get full text |
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Summary: | 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.
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•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. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 0161-5890 1872-9142 |
DOI: | 10.1016/j.molimm.2024.01.008 |