title: Lysophosphatidylcholine triggers TLR2- and TLR4-mediated signaling pathways but counteracts LPS-induced NO synthesis in peritoneal macrophages by inhibiting NF-κB translocation and MAPK/ERK phosphorylation.
abstract: BACKGROUND
  Lysophosphatidylcholine (LPC) is the main phospholipid component of oxidized low-density lipoprotein (oxLDL) and is usually noted as a marker of several human diseases, such as atherosclerosis, cancer and diabetes. Some studies suggest that oxLDL modulates Toll-like receptor (TLR) signaling. However, effector molecules that are present in oxLDL particles and can trigger TLR signaling are not yet clear. LPC was previously described as an attenuator of sepsis and as an immune suppressor. In the present study, we have evaluated the role of LPC as a dual modulator of the TLR-mediated signaling pathway.
  
  
  RESULTS
  HEK 293A cells were transfected with TLR expression constructs and stimulated with LPC molecules with different fatty acid chain lengths and saturation levels. All LPC molecules activated both TLR4 and TLR2-1 signaling, as evaluated by NF-қB activation and IL-8 production. These data were confirmed by Western blot analysis of NF-қB translocation in isolated nuclei of peritoneal murine macrophages. However, LPC counteracted the TLR4 signaling induced by LPS. In this case, NF-қB translocation, nitric oxide (NO) synthesis and the expression of inducible nitric oxide synthase (iNOS) were blocked. Moreover, LPC activated the MAP Kinases p38 and JNK, but not ERK, in murine macrophages. Interestingly, LPC blocked LPS-induced ERK activation in peritoneal macrophages but not in TLR-transfected cells.
  
  
  CONCLUSIONS
  The above results indicate that LPC is a dual-activity ligand molecule. It is able to trigger a classical proinflammatory phenotype by activating TLR4- and TLR2-1-mediated signaling. However, in the presence of classical TLR ligands, LPC counteracts some of the TLR-mediated intracellular responses, ultimately inducing an anti-inflammatory phenotype; LPC may thus play a role in the regulation of cell immune responses and disease progression.
authors: Instituto de Bioquímica Médica, Programa de Biologia Molecular e Biotecnologia, CCS, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Rio de Janeiro, Brazil ; Instituto Nacional de Ciência e Tecnologia em Entomologia Molecular- INCT-EM, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Rio de Janeiro, Brazil.
authors: Alan Brito
authors: AB
authors: Carneiro
authors: Bruna Maria Ferreira
authors: BM
authors: Iaciura
authors: Lilian Lie
authors: LL
authors: Nohara
authors: Carla Duque
authors: CD
authors: Lopes
authors: Esteban Mauricio Cordero
authors: EM
authors: Veas
authors: Vania Sammartino
authors: VS
authors: Mariano
authors: Patricia Torres
authors: PT
authors: Bozza
authors: Ulisses Gazos
authors: UG
authors: Lopes
authors: Georgia Correa
authors: GC
authors: Atella
authors: Igor Correia
authors: IC
authors: Almeida
authors: Mário Alberto Cardoso
authors: MA
authors: Silva-Neto
mesh_terms: D000818:Animals; D004336:Drug Antagonism; D004789:Enzyme Activation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D008070:Lipopolysaccharides / Q000276:immunology / Q000494:pharmacology; D008244:Lysophosphatidylcholines / Q000494:pharmacology*; D017737:Macrophages, Peritoneal / Q000276:immunology / Q000378:metabolism*; D008297:Male; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D009569:Nitric Oxide / Q000096:biosynthesis*; D010766:Phosphorylation / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects*; D051195:Toll-Like Receptor 2 / Q000235:genetics / Q000378:metabolism*; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism*
chemical_list: D008070:Lipopolysaccharides; D008244:Lysophosphatidylcholines; D016328:NF-kappa B; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D009569:Nitric Oxide; D048049:Extracellular Signal-Regulated MAP Kinases; D020928:Mitogen-Activated Protein Kinases