CD11/CD18 and CD14 share a common lipid A signaling pathway.
The activation of phagocytes by the lipid A moiety of LPS has been implicated in the pathogenesis of Gram-negative sepsis. While two LPS receptors, CD14 and CD11/CD18, have been associated with cell signaling, details of the LPS signal transduction cascade remain obscure. CD14, which exists as a GPI-anchored and a soluble protein, lacks cytoplasmic-signaling domains, suggesting that an ancillary molecule is required to activate cells. The CD11/CD18 integrins are transmembrane proteins. Like CD14, they are capable of mediating LPS-induced cellular activation when expressed on the surface of hamster fibroblasts Chinese hamster ovary (CHO)-K1. The observation that a cytoplasmic deletion mutant is still capable of activating transfected CHO-K1 argues that CD11/CD18 also utilizes an associated signal transducer. We sought to identify further similarities between the signaling systems utilized by CD14 and CD11/CD18. LPS-binding protein, which transfers LPS to CD14, enhanced both LPS-induced cellular activation and binding of Gram-negative bacteria in CD11/CD18-transfected CHO-K1, thus implying that LPS-binding protein can also transfer LPS to CD11/CD18. When synthetic lipid A analogues were analyzed for their ability to function as LPS agonists, or antagonists, in the CHO transfectants, we found the effects were identical regardless of which LPS receptor was expressed. This supports the hypothesis that a receptor distinct from CD14 and CD11/CD18 is responsible for discriminating between the lipid A of LPS and the LPS antagonists. We propose that this receptor, which is the target of the LPS antagonists, functions as the true signal transducer in LPS-induced cellular activation for both CD14 and CD11/CD18.
Ingalls
R R
RR
Department of Medicine, Boston Medical Center, Boston University School of Medicine, MA 02118, USA.
Monks
B G
BG
Savedra
R
R
Christ
W J
WJ
Delude
R L
RL
Medvedev
A E
AE
Espevik
T
T
Golenbock
D T
DT
D000209:Acute-Phase Proteins; D000818:Animals; D018845:CD11 Antigens / Q000235:genetics / Q000502:physiology*; D018821:CD18 Antigens / Q000502:physiology*; D016466:CHO Cells; D002352:Carrier Proteins / Q000502:physiology; D002460:Cell Line; D006224:Cricetinae; D006090:Gram-Negative Bacteria / Q000276:immunology; D006801:Humans; D008050:Lipid A / Q000031:analogs & derivatives / Q000502:physiology*; D018950:Lipopolysaccharide Receptors / Q000502:physiology*; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D008262:Macrophage Activation / Q000187:drug effects; D008562:Membrane Glycoproteins; D051379:Mice; D009161:Mycobacterium / Q000276:immunology; D010457:Peptidoglycan / Q000494:pharmacology; D015398:Signal Transduction / Q000276:immunology*; D014162:Transfection / Q000187:drug effects / Q000276:immunology; D014407:Tumor Cells, Cultured; D000099231:Lipopolysaccharide-Binding Protein
D000209:Acute-Phase Proteins; D018845:CD11 Antigens; D018821:CD18 Antigens; D002352:Carrier Proteins; D008050:Lipid A; D018950:Lipopolysaccharide Receptors; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D010457:Peptidoglycan; D000099231:Lipopolysaccharide-Binding Protein; C050016:lipoarabinomannan; C115671:B 1287