title: LPS induces IL-10 production by human alveolar macrophages via MAPKinases- and Sp1-dependent mechanisms.
abstract: BACKGROUND
  IL-10 is a cytokine mainly produced by macrophages that plays key roles in tolerance to inhaled antigens and in lung homeostasis. Its regulation in alveolar macrophages (HAM), the resident lung phagocytes, remains however unknown.
  
  
  METHODS
  The present study investigated the role of intracellular signalling and transcription factors controlling the production of IL-10 in LPS-activated HAM from normal nonsmoking volunteers.
  
  
  RESULTS
  LPS (1-1000 pg/ml) induced in vitro IL-10 production by HAM, both at mRNA and protein levels. LPS also activated the phosphorylation of ERK, p38 and JNK MAPkinases (immunoblots) and Sp-1 nuclear activity (EMSA). Selective inhibitors of MAPKinases (respectively PD98059, SB203580 and SP600125) and of Sp-1 signaling (mithramycin) decreased IL-10 expression in HAM. In addition, whilst not affecting IL-10 mRNA degradation, the three MAPKinase inhibitors completely abolished Sp-1 activation by LPS in HAM.
  
  
  CONCLUSIONS
  These results demonstrate for the first time that expression of IL-10 in lung macrophages stimulated by LPS depends on the concomitant activation of ERK, p38 and JNK MAPKinases, which control downstream signalling to Sp-1 transcription factor. This study further points to Sp-1 as a key signalling pathway for IL-10 expression in the lung.
authors.affiliation: Unit of microbiology, Université Catholique de Louvain, Av Hippocrate 54, B-1200 Brussels, Belgium. hugues.chanteux@ucb-group.com
authors.forename: Hugues
authors.initials: H
authors.lastname: Chanteux
authors.forename: Amélie C
authors.initials: AC
authors.lastname: Guisset
authors.forename: Charles
authors.initials: C
authors.lastname: Pilette
authors.forename: Yves
authors.initials: Y
authors.lastname: Sibille
mesh_terms: D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D016753:Interleukin-10 / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology*; D016676:Macrophages, Alveolar / Q000187:drug effects* / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000378:metabolism*; D019384:Nucleic Acid Synthesis Inhibitors / Q000494:pharmacology; D008926:Plicamycin / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D016329:Sp1 Transcription Factor / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D008070:Lipopolysaccharides; D019384:Nucleic Acid Synthesis Inhibitors; D012333:RNA, Messenger; D016329:Sp1 Transcription Factor; D016753:Interleukin-10; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D008926:Plicamycin