title: Leishmania mexicana lipophosphoglycan activates ERK and p38 MAP kinase and induces production of proinflammatory cytokines in human macrophages through TLR2 and TLR4.
abstract: Protozoan parasites of genus Leishmania are the causative agents of leishmaniasis. Leishmania promastigotes primarily infect macrophages in the host, where they transform into amastigotes and multiply. Lipophosphoglycan (LPG), the most abundant surface molecule of the parasite, is a virulence determinant that regulates the host immune response. Promastigotes are able to modulate this effect through LPG, creating a favourable environment for parasite survival, although the mechanisms underlying this modulation remain unknown. We analysed the participation of TLR2 and TLR4 in the production of cytokines and explored the possible phosphorylation of ERK and/or p38 MAP kinase signalling cascades in human macrophages stimulated with Leishmania mexicana LPG. The results show that LPG induced the production of TNF-α, IL-1β, IL-12p40, IL-12p70 and IL-10 and led to phosphorylation of ERK and p38 MAP kinase. Specific inhibitors of ERK or p38 MAP kinases and mAbs against TLR2 and TLR4 reduced cytokine production and phosphorylation of both kinases. Our results suggest that L. mexicana LPG binds TLR2 and TLR4 receptors in human macrophages, leading to ERK and MAP kinase phosphorylation and production of pro-inflammatory cytokines.
authors: Departamento de Medicina Experimental, Facultad de Medicina, Universidad Nacional Autónoma de México, México, D.F., México.
authors: A
authors: A
authors: Rojas-Bernabé
authors: Departamento de Medicina Experimental, Facultad de Medicina, Universidad Nacional Autónoma de México, México, D.F., México.
authors: O
authors: O
authors: Garcia-Hernández
authors: Unidad de Investigación de Enfermedades Oncológicas, Hospital Infantil de México Federico Gómez, México, D.F., México.
authors: C
authors: C
authors: Maldonado-Bernal
authors: Departamento de Medicina Experimental, Facultad de Medicina, Universidad Nacional Autónoma de México, México, D.F., México.
authors: J
authors: J
authors: Delegado-Dominguez
authors: Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, México, D.F., México.
authors: E
authors: E
authors: Ortega
authors: Departamento de Medicina Experimental, Facultad de Medicina, Universidad Nacional Autónoma de México, México, D.F., México.
authors: L
authors: L
authors: Gutiérrez-Kobeh
authors: Departamento de Medicina Experimental, Facultad de Medicina, Universidad Nacional Autónoma de México, México, D.F., México.
authors: I
authors: I
authors: Becker
authors: Departamento de Medicina Experimental, Facultad de Medicina, Universidad Nacional Autónoma de México, México, D.F., México.
authors: M
authors: M
authors: Aguirre-Garcia
mesh_terms: D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D006028:Glycosphingolipids; D006801:Humans; D007894:Leishmania mexicana / Q000276:immunology* / Q000472:pathogenicity; D007896:Leishmaniasis / Q000276:immunology* / Q000469:parasitology; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D010766:Phosphorylation; D051195:Toll-Like Receptor 2 / Q000235:genetics / Q000378:metabolism*; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: D016207:Cytokines; D006028:Glycosphingolipids; C495342:TLR2 protein, human; C495345:TLR4 protein, human; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; C008290:lipophosphonoglycan; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases