title: LPS induces the degradation of programmed cell death protein 4 (PDCD4) to release Twist2, activating c-Maf transcription to promote interleukin-10 production.
abstract: Programmed cell death protein 4 (PDCD4) is a tumor suppressor and has also been shown to suppress production of the immunomodulatory cytokine IL-10. The precise role of PDCD4 in IL-10 induction in macrophages is still not fully understood. Incubation of macrophages with inhibitors of PI3K and mTOR blocked LPS-stimulated PDCD4 degradation and expression of c-Maf and IL-10 production. PDCD4 and the transcription factor Twist2 were shown to form a complex in untreated cells. LPS disrupted the complex allowing Twist2 to bind to the c-Maf promoter. PI3K and mTOR inhibitors prevented this disruption by stabilizing PDCD4 and thereby decreased Twist2 binding to the c-Maf promoter and induction of c-Maf mRNA. These results indicate a regulatory role for PDCD4 and Twist2 in LPS-induced IL-10 production in macrophages. LPS promotes PDCD4 degradation via a pathway involving PI3K and mTOR, releasing Twist2, which induces IL-10 via c-Maf.
authors: School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland and. Electronic address: vandenbm@tcd.ie.
authors: Mirjam W M
authors: MWM
authors: van den Bosch
authors: School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland and.
authors: Eva
authors: E
authors: Palsson-Mcdermott
authors: Department of Pathology and Laboratory Medicine, School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104.
authors: Derek S
authors: DS
authors: Johnson
authors: School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland and.
authors: Luke A J
authors: LAJ
authors: O'Neill
mesh_terms: D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D016753:Interleukin-10 / Q000096:biosynthesis* / Q000235:genetics; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008264:Macrophages / Q000166:cytology / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000502:physiology; D059748:Proteolysis / Q000187:drug effects*; D051257:Proto-Oncogene Proteins c-maf / Q000235:genetics / Q000378:metabolism*; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects* / Q000502:physiology; D051879:Twist-Related Protein 1 / Q000235:genetics / Q000378:metabolism*
chemical_list: D051017:Apoptosis Regulatory Proteins; D016753:Interleukin-10; D008070:Lipopolysaccharides; D019869:Phosphatidylinositol 3-Kinases; D051257:Proto-Oncogene Proteins c-maf; D016601:RNA-Binding Proteins; D012097:Repressor Proteins; D058570:TOR Serine-Threonine Kinases; D051879:Twist-Related Protein 1; C508609:IL10 protein, human; C495607:MAF protein, human; C114487:PDCD4 protein, human; C486274:TWIST2 protein, human; C440499:lipopolysaccharide, Escherichia coli O111 B4; C546842:MTOR protein, human
keywords: IL-10; Inflammation; Interleukin; Lipopolysaccharide (LPS); PDCD4; Rapamycin; Transcription Factor; Twist2; c-maf; mTOR Complex (mTORC)