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Signaling pathways underlying TGF-β mediated suppression of IL-12A gene expression in monocytes
Tetiana Hourani1, Mahtab Eivazitork1, Thivya Balendran1
1Department of Medicine, Royal Melbourne Hospital, The University of Melbourne, Parkville, VIC 3052, Australia.
Molecular Immunology
|January 26, 2024
Summary
Transforming growth factor-β (TGF-β) complexly regulates interleukin-12A (IL-12A) gene expression in monocytes via Smad2/3, NF-κB, and JNK1/2 pathways. Understanding these pathways offers new therapeutic targets for increasing IL-12 in tumors.
Area of Science:
- Immunology
- Molecular Biology
- Cell Signaling
Background:
- Transforming growth factor-β (TGF-β) is a key regulator of immune responses.
- Interleukin-12 (IL-12) is critical for anti-tumor immunity, but its regulation is not fully understood.
- The IL-12A gene, encoding the IL-12p35 subunit, has limited known regulatory mechanisms.
Purpose of the Study:
- To investigate the molecular regulation of IL-12A gene expression by TGF-β-activated signaling pathways.
- To identify specific signaling cascades involved in controlling IL-12A expression in THP-1 monocytes.
- To explore potential therapeutic targets for modulating IL-12 levels.
Main Methods:
- Utilized THP-1 monocytes as a cellular model.
- Employed pharmacological inhibitors and genetic manipulation (Smad7 overexpression) to block specific signaling pathways.
- Assessed IL-12A gene expression changes in response to pathway modulation.
Main Results:
- TGF-β exhibits complex regulation of IL-12A expression.
- NF-κB signaling inhibition decreased IL-12A expression.
- Smad2/3 and JNK1/2 pathway inhibition/blockade increased IL-12A expression.
Conclusions:
- TGF-β regulates IL-12A via Smad2/3, NF-κB, p38, and JNK1/2 signaling.
- Targeting these pathways can modulate IL-12A expression.
- Findings suggest novel therapeutic strategies for enhancing IL-12 in the tumor microenvironment.
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