title: Differential IL-1β secretion by monocyte subsets is regulated by Hsp27 through modulating mRNA stability.
abstract: Monocytes play a central role in regulating inflammation in response to infection or injury, and during auto-inflammatory diseases. Human blood contains classical, intermediate and non-classical monocyte subsets that each express characteristic patterns of cell surface CD16 and CD14; each subset also has specific functional properties, but the mechanisms underlying many of their distinctive features are undefined. Of particular interest is how monocyte subsets regulate secretion of the apical pro-inflammatory cytokine IL-1β, which is central to the initiation of immune responses but is also implicated in the pathology of various auto-immune/auto-inflammatory conditions. Here we show that primary human non-classical monocytes, exposed to LPS or LPS + BzATP (3'-O-(4-benzoyl)benzyl-ATP, a P2X7R agonist), produce approx. 80% less IL-1β than intermediate or classical monocytes. Despite their low CD14 expression, LPS-sensing, caspase-1 activation and P2X7R activity were comparable in non-classical monocytes to other subsets: their diminished ability to produce IL-1β instead arose from 50% increased IL-1β mRNA decay rates, mediated by Hsp27. These findings identify the Hsp27 pathway as a novel therapeutic target for the management of conditions featuring dysregulated IL-1β production, and represent an advancement in understanding of both physiological inflammatory responses and the pathogenesis of inflammatory diseases involving monocyte-derived IL-1β.
authors.affiliation: University of Sheffield, Dept of Infection, Immunity &Cardiovascular Disease (IICD), Sheffield, UK.|Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (ASTAR), Singapore.
authors.forename: Eva
authors.initials: E
authors.lastname: Hadadi
authors.affiliation: Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (ASTAR), Singapore.
authors.forename: Biyan
authors.initials: B
authors.lastname: Zhang
authors.affiliation: University of Sheffield, Dept of Infection, Immunity &Cardiovascular Disease (IICD), Sheffield, UK.
authors.forename: Kajus
authors.initials: K
authors.lastname: Baidžajevas
authors.affiliation: Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (ASTAR), Singapore.
authors.forename: Nurhashikin
authors.initials: N
authors.lastname: Yusof
authors.affiliation: Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (ASTAR), Singapore.
authors.forename: Kia Joo
authors.initials: KJ
authors.lastname: Puan
authors.affiliation: Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (ASTAR), Singapore.
authors.forename: Siew Min
authors.initials: SM
authors.lastname: Ong
authors.affiliation: Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (ASTAR), Singapore.
authors.forename: Wei Hseun
authors.initials: WH
authors.lastname: Yeap
authors.affiliation: Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (ASTAR), Singapore.
authors.forename: Olaf
authors.initials: O
authors.lastname: Rotzschke
authors.affiliation: University of Sheffield, Dept of Infection, Immunity &Cardiovascular Disease (IICD), Sheffield, UK.
authors.forename: Endre
authors.initials: E
authors.lastname: Kiss-Toth
authors.affiliation: University of Sheffield, Dept of Infection, Immunity &Cardiovascular Disease (IICD), Sheffield, UK.
authors.forename: Heather
authors.initials: H
authors.lastname: Wilson
authors.affiliation: Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (ASTAR), Singapore.
authors.forename: Siew Cheng
authors.initials: SC
authors.lastname: Wong
mesh_terms: D000255:Adenosine Triphosphate / Q000031:analogs & derivatives / Q000494:pharmacology; D002478:Cells, Cultured; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D055551:HSP27 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000378:metabolism; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology; D009000:Monocytes / Q000187:drug effects* / Q000378:metabolism; D034622:RNA Interference; D020871:RNA Stability / Q000187:drug effects / Q000235:genetics
chemical_list: D016207:Cytokines; D055551:HSP27 Heat-Shock Proteins; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; C033901:3'-O-(4-benzoyl)benzoyladenosine 5'-triphosphate; D000255:Adenosine Triphosphate