title: Involvement of RNA Polymerase III in Immune Responses.
abstract: Inflammation in the tumor microenvironment has many tumor-promoting effects. In particular, tumor-associated macrophages (TAMs) produce many cytokines which can support tumor growth by promoting survival of malignant cells, angiogenesis, and metastasis. Enhanced cytokine production by TAMs is tightly coupled with protein synthesis. In turn, translation of proteins depends on tRNAs, short abundant transcripts that are made by RNA polymerase III (Pol III). Here, we connect these facts by showing that stimulation of mouse macrophages with lipopolysaccharides (LPS) from the bacterial cell wall causes transcriptional upregulation of tRNA genes. The transcription factor NF-κB is a key transcription factor mediating inflammatory signals, and we report that LPS treatment causes an increased association of the NF-κB subunit p65 with tRNA genes. In addition, we show that p65 can directly associate with the Pol III transcription factor TFIIIB and that overexpression of p65 induces Pol III-dependent transcription. As a consequence of these effects, we show that inhibition of Pol III activity in macrophages restrains cytokine secretion and suppresses phagocytosis, two key functional characteristics of these cells. These findings therefore identify a radical new function for Pol III in the regulation of macrophage function which may be important for the immune responses associated with both normal and malignant cells.
authors.affiliation: Cancer Research UK Beatson Institute, Glasgow, United Kingdom d.graczyk@beatson.gla.ac.uk k.ryan@beatson.gla.ac.uk.
authors.forename: Damian
authors.initials: D
authors.lastname: Graczyk
authors.affiliation: Department of Biology, University of York, York, United Kingdom.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: White
authors.affiliation: Cancer Research UK Beatson Institute, Glasgow, United Kingdom d.graczyk@beatson.gla.ac.uk k.ryan@beatson.gla.ac.uk.
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Ryan
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D016207:Cytokines / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007113:Immunity, Innate; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects*; D051379:Mice; D010587:Phagocytosis; D012320:RNA Polymerase III / Q000378:metabolism*; D012343:RNA, Transfer / Q000378:metabolism*; D051996:Transcription Factor RelA / Q000378:metabolism*; D035361:Transcription Factor TFIIIB / Q000378:metabolism; D059016:Tumor Microenvironment
chemical_list: D016207:Cytokines; D008070:Lipopolysaccharides; C498144:Rela protein, mouse; D051996:Transcription Factor RelA; D035361:Transcription Factor TFIIIB; D012343:RNA, Transfer; D012320:RNA Polymerase III