Differential regulation of lipopolysaccharide (LPS) activation pathways in mouse macrophages by LPS-binding proteins.
LPS binding to its receptor(s) on macrophages induces the synthesis of inflammatory mediators involved in septic shock. While the signaling mechanism(s) remains to be fully defined, the human LPS-binding protein (LBP) is known to regulate responses to LPS by facilitating its binding to CD14 on human monocytes. The structurally related bactericidal permeability increasing protein (BPI) differs from LBP by inhibiting LPS-induced human monocyte activation. We have demonstrated that, unlike the human monocyte response to LPS, both LBP and BPI inhibited LPS-stimulated TNF-alpha production in mouse peritoneal macrophages. In contrast, LPS-dependent nitric oxide release was not affected by LBP. LPS induces the phosphorylation of a number of proteins in a dose and time-dependent manner, however, the pattern of LPS-induced phosphorylation was not reduced by either LBP or BPI under conditions that result in selective TNF-alpha inhibition. Further, activation of the transcription factor NF-kappaB in response to LPS was also not modified by either LBP or BPI. Finally, no differences were detected in TNF-alpha or inducible nitric oxide synthase mRNA accumulations induced by LPS in the presence or absence of either protein, whereas a slight decreased mRNA stability was observed in the group with LPS treatment. These results would suggest that many of the early signaling events contribute to LPS-induced macrophage signaling at a point preceding the divergence of pathways that differentially regulate TNF-alpha and NO production.
Amura
C R
CR
Department of Microbiology, Molecular Genetics, and Immunology, University of Kansas Medical Center, Kansas City 66160, USA.
Kamei
T
T
Ito
N
N
Soares
M J
MJ
Morrison
D C
DC
D000209:Acute-Phase Proteins; D000818:Animals; D023181:Antimicrobial Cationic Peptides; D001692:Biological Transport / Q000187:drug effects / Q000235:genetics; D001798:Blood Proteins / Q000494:pharmacology; D002352:Carrier Proteins / Q000494:pharmacology*; D016207:Cytokines / Q000235:genetics; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D007700:Kinetics; D008070:Lipopolysaccharides / Q000378:metabolism / Q000494:pharmacology*; D008262:Macrophage Activation / Q000187:drug effects*; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D051379:Mice; D008809:Mice, Inbred C3H; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D013997:Time Factors; D014157:Transcription Factors / Q000187:drug effects / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects / Q000276:immunology; D000099231:Lipopolysaccharide-Binding Protein
D000209:Acute-Phase Proteins; D023181:Antimicrobial Cationic Peptides; D001798:Blood Proteins; D002352:Carrier Proteins; D016207:Cytokines; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D011505:Protein-Tyrosine Kinases; D014157:Transcription Factors; D000099231:Lipopolysaccharide-Binding Protein; C021623:bactericidal permeability increasing protein