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

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

  • Mol Immunol. 2024 Feb:166:101-109. doi: 10.1016/j.molimm.2024.01.008.
Tetiana Hourani 1,  Mahtab Eivazitork 1,  Thivya Balendran 1,  Kevin Mc Lee 1,  John A Hamilton 1,  Hong-Jian Zhu 2,  Josephine Iaria 2,  Andrew P Morokoff 3,  Rodney B Luwor 4,  Adrian A Achuthan 5
Affiliations

Affiliations

  • 1 Department of Medicine, Royal Melbourne Hospital, The University of Melbourne, Parkville, VIC 3052, Australia.
  • 2 Department of Surgery, Royal Melbourne Hospital, The University of Melbourne, Parkville, VIC 3052, Australia.
  • 3 Department of Surgery, Royal Melbourne Hospital, The University of Melbourne, Parkville, VIC 3052, Australia; Department of Neurosurgery, Royal Melbourne Hospital, Parkville, VIC 3050, Australia.
  • 4 Department of Surgery, Royal Melbourne Hospital, The University of Melbourne, Parkville, VIC 3052, Australia; Fiona Elsey Cancer Research Institute, Ballarat, VIC 3350, Australia; Federation University, Ballarat, VIC 3350, Australia.
  • 5 Department of Medicine, Royal Melbourne Hospital, The University of Melbourne, Parkville, VIC 3052, Australia. Electronic address: [email protected].
PMID: 38278031 DOI: 10.1016/j.molimm.2024.01.008
Abstract

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.

Keywords

Glioblastoma; IL-12; Inflammation; Monocytes; Signaling; TGF-β.

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