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
{"title":"TGF-β 介导的抑制单核细胞 IL-12A 基因表达的信号通路","authors":"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","doi":"10.1016/j.molimm.2024.01.008","DOIUrl":null,"url":null,"abstract":"<div><p>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 <em>IL-12B</em> gene) of IL-12 has been extensively investigated, the knowledge of IL-12p35 (encoded by <em>IL-12A</em> gene) subunit regulation is relatively limited. This study investigates the molecular regulation of <em>IL-12A</em> by TGF-β-activated signaling pathways in THP-1 monocytes. Our study identifies a complex regulation of <em>IL-12A</em> 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 <em>IL-12A</em> 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 <em>IL-12A</em> gene expression potentially provide new therapeutic targets to increase IL-12 levels in the tumor microenvironment.</p></div>","PeriodicalId":18938,"journal":{"name":"Molecular immunology","volume":"166 ","pages":"Pages 101-109"},"PeriodicalIF":3.2000,"publicationDate":"2024-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0161589024000166/pdfft?md5=f843cd07e9ac7fd8c064d36102fc02f8&pid=1-s2.0-S0161589024000166-main.pdf","citationCount":"0","resultStr":"{\"title\":\"Signaling pathways underlying TGF-β mediated suppression of IL-12A gene expression in monocytes\",\"authors\":\"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\",\"doi\":\"10.1016/j.molimm.2024.01.008\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><p>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 <em>IL-12B</em> gene) of IL-12 has been extensively investigated, the knowledge of IL-12p35 (encoded by <em>IL-12A</em> gene) subunit regulation is relatively limited. This study investigates the molecular regulation of <em>IL-12A</em> by TGF-β-activated signaling pathways in THP-1 monocytes. Our study identifies a complex regulation of <em>IL-12A</em> 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 <em>IL-12A</em> 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 <em>IL-12A</em> gene expression potentially provide new therapeutic targets to increase IL-12 levels in the tumor microenvironment.</p></div>\",\"PeriodicalId\":18938,\"journal\":{\"name\":\"Molecular immunology\",\"volume\":\"166 \",\"pages\":\"Pages 101-109\"},\"PeriodicalIF\":3.2000,\"publicationDate\":\"2024-02-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.sciencedirect.com/science/article/pii/S0161589024000166/pdfft?md5=f843cd07e9ac7fd8c064d36102fc02f8&pid=1-s2.0-S0161589024000166-main.pdf\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Molecular immunology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S0161589024000166\",\"RegionNum\":3,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"BIOCHEMISTRY & MOLECULAR BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Molecular immunology","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0161589024000166","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
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.
期刊介绍:
Molecular Immunology publishes original articles, reviews and commentaries on all areas of immunology, with a particular focus on description of cellular, biochemical or genetic mechanisms underlying immunological phenomena. Studies on all model organisms, from invertebrates to humans, are suitable. Examples include, but are not restricted to:
Infection, autoimmunity, transplantation, immunodeficiencies, inflammation and tumor immunology
Mechanisms of induction, regulation and termination of innate and adaptive immunity
Intercellular communication, cooperation and regulation
Intracellular mechanisms of immunity (endocytosis, protein trafficking, pathogen recognition, antigen presentation, etc)
Mechanisms of action of the cells and molecules of the immune system
Structural analysis
Development of the immune system
Comparative immunology and evolution of the immune system
"Omics" studies and bioinformatics
Vaccines, biotechnology and therapeutic manipulation of the immune system (therapeutic antibodies, cytokines, cellular therapies, etc)
Technical developments.