title: Hlx homeobox transcription factor negatively regulates interferon-gamma production in monokine-activated natural killer cells.
abstract: Natural killer (NK) cells contribute to host immunity, including tumor surveillance, through the production of interferon gamma (IFN-gamma). Although there is some knowledge about molecular mechanisms that induce IFN-gamma in NK cells, considerably less is known about the mechanisms that reduce its expression. Here, we investigate the role of the Hlx transcription factor in IFN-gamma production by NK cells. Hlx expression is induced in monokine-activated NK cells, but with delayed kinetics compared to IFN-gamma. Ectopic Hlx expression decreases IFN-gamma synthesis in primary human NK cells and IFN-gamma promoter activity in an NK-like cell line. Hlx protein levels inversely correlate with those of STAT4, a requisite factor for optimal IFN-gamma transcription. Mechanistically, we provide evidence indicating that Hlx overexpression accelerates dephosphorylation and proteasome-dependent degradation of the active Y693-phosphorylated form of STAT4. Thus, Hlx expression in activated NK cells temporally controls and limits the monokine-induced production of IFN-gamma, in part through the targeted depletion of STAT4.
authors.affiliation: Medical Scientist Program, Department of Internal Medicine, College of Medicine and Public Health, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: Brian
authors.initials: B
authors.lastname: Becknell
authors.forename: Tiffany L
authors.initials: TL
authors.lastname: Hughes
authors.forename: Aharon G
authors.initials: AG
authors.lastname: Freud
authors.forename: Bradley W
authors.initials: BW
authors.lastname: Blaser
authors.forename: Jianhua
authors.initials: J
authors.lastname: Yu
authors.forename: Rossana
authors.initials: R
authors.lastname: Trotta
authors.forename: Hsiaoyin C
authors.initials: HC
authors.lastname: Mao
authors.forename: Marie L
authors.initials: ML
authors.lastname: Caligiuri de Jesús
authors.forename: Mohamad
authors.initials: M
authors.lastname: Alghothani
authors.forename: Don M
authors.initials: DM
authors.lastname: Benson
authors.forename: Amy
authors.initials: A
authors.lastname: Lehman
authors.forename: David
authors.initials: D
authors.lastname: Jarjoura
authors.forename: Danilo
authors.initials: D
authors.lastname: Perrotti
authors.forename: Michael D
authors.initials: MD
authors.lastname: Bates
authors.forename: Michael A
authors.initials: MA
authors.lastname: Caligiuri
mesh_terms: D000818:Animals; D002460:Cell Line; D015536:Down-Regulation; D005801:Genes, Homeobox / Q000235:genetics; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis* / Q000235:genetics; D007694:Killer Cells, Natural / Q000187:drug effects* / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D015846:Monokines / Q000494:pharmacology*; D011401:Promoter Regions, Genetic / Q000235:genetics; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D050797:STAT4 Transcription Factor / Q000378:metabolism; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
chemical_list: C084058:HLX protein, human; C489999:Hlx protein, mouse; D018398:Homeodomain Proteins; D015846:Monokines; D050797:STAT4 Transcription Factor; D014157:Transcription Factors; D007371:Interferon-gamma; D046988:Proteasome Endopeptidase Complex