CD11/CD18 and CD14 share a common lipid A signaling pathway

The activation of phagocytes by the lipid A moiety of LPS has been im plicated in the pathogenesis of Gram-negative sepsis. While two LPS r eceptors, CD14 and CD11/CD18, have been associated with cell signalin g, details of the LPS signal transduction cascade remain obscure. CD1 4, which exists as a GPI-anchored and a soluble protein, lacks cytopl asmic-signaling domains, suggesting that an ancillary molecule is req uired to activate cells. The CD11/CD18 integrins are transmembrane pr oteins. Like CD14, they are capable of mediating LPS-induced cellular activation when expressed on the surface of hamster fibroblasts Chin ese hamster ovary (CHO)-K1. The observation that a cytoplasmic deleti on mutant is still capable of activating transfected CHO-K1 argues th at CD11/CD18 also utilizes an associated signal transducer. We sought to identify further similarities between the signaling systems utili zed by CD14 and CD11/CD18. LPS-binding protein, which transfers LPS t o 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 sy nthetic 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 expre ssed. 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 tr ansducer in LPS-induced cellular activation for both CD14 and CD11/CD 18.