Interaction of endotoxins with Toll-like receptor 4 correlates with their endotoxic potential and may explain the proinflammatory effect of Brucella spp. LPS.
Endotoxins displaying differences in the chemical structure of their lipid A were used to induce the expression of chemokines in the human monocytic THP-1 cell line. LPS from two enterobacterial species such as Escherichia coli and Yersinia enterocolitica induced mRNA expression of IFN-gamma-inducible protein (IP)-10, macrophage-inflammatory protein (MIP)-1alpha, MIP-1beta, monocyte chemoattractant protein (MCP)-1 and IL-8. LPS from the non-enterobacterial genera Brucella and Ochrobactrum induced the expression of these chemokines to a lower extent. Attempts to address the signaling routes involved in these responses were carried out in transiently transfected HEK293 cells. Induction of kappaB-driven transcriptional activity by enterobacterial LPS was observed in cells transfected with TLR-4 alone, although co-transfection of TLR-4, MD-2 and CD14 provided optimal induction. The response to Brucella spp. and Ochrobactrum anthropi LPS was only significant at the concentration of 10 microg/ml. These data indicate that LPS from Brucella spp. and O. anthropi, which contain lipid A moieties with structural features different from those of Enterobacteriaceae elicit biochemical signaling via TLR-4 only at high concentrations. Neither TLR-1, TLR-2 and TLR-6 nor heterodimeric combinations of these receptor molecules are involved. Conversely, the ability of LPS to activate the TLR-4 route is a reliable molecular biomarker for endotoxicity.
Dueñas
Ana I
AI
Unidad de Investigación, Hospital Clínico Universitario, Valladolid, Spain.
Orduña
Antonio
A
Crespo
Mariano Sánchez
MS
García-Rodríguez
Carmen
C
D000818:Animals; D000954:Antigens, Surface / Q000276:immunology / Q000378:metabolism; D002002:Brucella / Q000276:immunology*; D002352:Carrier Proteins / Q000276:immunology / Q000378:metabolism; D002460:Cell Line; D018925:Chemokines / Q000276:immunology*; D004731:Endotoxins / Q000276:immunology* / Q000378:metabolism; D004926:Escherichia coli; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D008050:Lipid A / Q000276:immunology*; D018950:Lipopolysaccharide Receptors / Q000276:immunology / Q000378:metabolism; D008070:Lipopolysaccharides / Q000737:chemistry / Q000276:immunology / Q000494:pharmacology*; D051218:Lymphocyte Antigen 96; D008562:Membrane Glycoproteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D009000:Monocytes / Q000276:immunology; D042041:Ochrobactrum / Q000276:immunology; D012333:RNA, Messenger / Q000032:analysis; D011956:Receptors, Cell Surface / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D051194:Toll-Like Receptor 1; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D015533:Transcriptional Activation; D014162:Transfection
D000954:Antigens, Surface; D002352:Carrier Proteins; D018925:Chemokines; D004731:Endotoxins; C495377:LY96 protein, human; D008050:Lipid A; D018950:Lipopolysaccharide Receptors; D008070:Lipopolysaccharides; D051218:Lymphocyte Antigen 96; D008562:Membrane Glycoproteins; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; C495342:TLR2 protein, human; C495345:TLR4 protein, human; D051194:Toll-Like Receptor 1; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors