title: Leptin enhances the secretion of interleukin (IL)-18, but not IL-1β, from human monocytes via activation of caspase-1.
abstract: Circulating levels of leptin are elevated in type-2 diabetes mellitus (T2DM) and leptin plays a role in immune responses. Elevated circulating IL-18 levels are associated with clinical complications of T2DM. IL-18 regulates cytokine secretion and the function of a number of immune cells including T-cells, neutrophils and macrophages and as such has a key role in immunity and inflammation. Pro-inflammatory monocytes exhibiting elevated cytokine secretion are closely associated with inflammation in T2DM, however, little is known about the role of leptin in modifying monocyte IL-18 secretion. We therefore aimed to investigate the effect of leptin on IL-18 secretion by monocytes. We report herein that leptin increases IL-18 secretion in THP-1 and primary human monocytes but has no effect on IL-18mRNA. Leptin and LPS signalling in monocytes occurs by overlapping but distinct pathways. Thus, in contrast to a strong stimulation by LPS, leptin has no effect on IL-1βmRNA levels or IL-1β secretion. In addition, LPS stimulates the secretion of IL-6 but leptin did not whereas both treatments up regulate IL-8 secretion from the same cells. Although leptin (and LPS) has a synergistic effect with exogenous ATP on IL-18 secretion in both THP-1 and primary monocytes, experiments involving ATP assays and pharmacological inhibition of ATP signalling failed to provide any evidence that endogenous ATP secreted by leptin-stimulated monocytes was responsible for enhancement of monocyte IL-18 secretion by leptin. Analysis of the action of caspase-1 revealed that leptin up regulates caspase-1 activity and the effect of leptin on IL-18 release is prevented by caspase-1 inhibitor (Ac-YVAD-cmk). These data suggest that leptin activates IL-18 processing rather than IL-18 transcription. In conclusion, leptin enhances IL-18 secretion via modulation of the caspase-1 inflammasome function and acts synergistically with ATP in this regard. This process may contribute to aberrant immune responses in T2DM and other conditions of hyperleptinemia.
authors.affiliation: Centre for Oral Health Research and Institute of Cellular Medicine, Newcastle University, Framlington Place, Newcastle upon Tyne NE2 4BW, UK. Electronic address: paiboonj@nu.ac.th.
authors.forename: Paiboon
authors.initials: P
authors.lastname: Jitprasertwong
authors.affiliation: Centre for Oral Health Research and Institute of Cellular Medicine, Newcastle University, Framlington Place, Newcastle upon Tyne NE2 4BW, UK. Electronic address: katrin.jaedicke@ncl.ac.uk.
authors.forename: Katrin M
authors.initials: KM
authors.lastname: Jaedicke
authors.affiliation: Centre for Oral Health Research and Institute of Cellular Medicine, Newcastle University, Framlington Place, Newcastle upon Tyne NE2 4BW, UK. Electronic address: christopher.nile@glasgow.ac.uk.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Nile
authors.affiliation: Centre for Oral Health Research and Institute of Cellular Medicine, Newcastle University, Framlington Place, Newcastle upon Tyne NE2 4BW, UK. Electronic address: philip.preshaw@ncl.ac.uk.
authors.forename: Philip M
authors.initials: PM
authors.lastname: Preshaw
authors.affiliation: Centre for Oral Health Research and Institute of Cellular Medicine, Newcastle University, Framlington Place, Newcastle upon Tyne NE2 4BW, UK. Electronic address: john.taylor@ncl.ac.uk.
authors.forename: John J
authors.initials: JJ
authors.lastname: Taylor
mesh_terms: D000255:Adenosine Triphosphate / Q000494:pharmacology; D020170:Caspase 1 / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D020382:Interleukin-18 / Q000235:genetics / Q000378:metabolism*; D053583:Interleukin-1beta / Q000378:metabolism*; D020738:Leptin / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D009000:Monocytes / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: C508585:IL1B protein, human; D020382:Interleukin-18; D053583:Interleukin-1beta; D020738:Leptin; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D000255:Adenosine Triphosphate; D020170:Caspase 1
keywords: Caspase-1; E. coli; Escherichia coli; G-CSF; Inflammation; Interleukin-18; JAK2; LPS; Leptin; MAPK; MDDC; Monocytes; NLR-family, pyrin containing 3; NLRP3; PAMPs; PI3K; PPADS; STAT; T helper 1; T helper 2; T2DM; Th1; Th2; granulocyte-colony stimulating factor; janus kinase 2; lipopolysaccharide; mitogen-activated protein kinases; monocyte-derived dendritic cells; pathogen-activated molecular patterns; phosphoinositide 3-kinase; pyrodoxal phosphor-6azo (benzene-2, 4-disulfonic acid) tetrasodium salt hydrate; signal transducer and activator of transcription; type-2 diabetes mellitus