Influence of CD14 on Ligand Interactions between Lipopolysaccharide and Its Receptor Complex

Abstract

The interaction of LPS (endotoxin) with the CD14-TLR4 receptor complex modulates the host innate immune response. Several studies using partial structures of LPS have suggested that TLR4 determines the ligand specificity of this complex, and that CD14 indiscriminately serves to deliver the ligand to TLR4. This conclusion has been made despite observations that the response of TLR4+/+,CD14−/− macrophages to LPS is very weak. To determine whether CD14 itself plays a role in specific ligand recognition, the influences of various partial structures of LPS on induction of the proinflammatory cytokine, TNF, by CD14+/+ and CD14−/− macrophages were compared. These studies show that the ligand specificities of CD14+/+ and CD14−/− macrophages are very different. When CD14 is present, the receptor complex shows exquisite specificity for smooth LPS, the major form expressed by Gram-negative bacteria; however, as increasing amounts of carbohydrate are removed from smooth LPS, the sensitivity of CD14+/+ macrophages decreases as much as 500-fold. In contrast, CD14−/− macrophages are unable to distinguish between smooth LPS and its various partial structures. Furthermore, CD14−/− macrophages are 150,000-fold less sensitive than CD14+/+ macrophages to smooth LPS. A similar ability to distinguish the differing LPS structures of various bacteria such as Bacteroides fragilis and Salmonella abortus are observed for CD14+/+, but not CD14−/−, macrophages. Thus, CD14+/+, but not CD14−/−, macrophages are highly sensitive to stimulation by natural forms of LPS and show the ability to distinguish between various LPS ligands, consistent with CD14 being a highly specific receptor.

Candidate inhibitors of porcine complement

“…LPS from E. coli strains are smooth (159). CD14 would according to these findings by Jiang and Gangloff (41,47), be essential for recognition of and signaling by the E. coli LPS used in study II, III and V in this Thesis. Inhibiting CD14 in order to reduce smooth LPS-induced inflammatory responses might therefore be more effective than inhibiting TLR4.…”

“…CD14 was detected earlier than the TLRs and found to bind the complex of LPS bound to the plasma LPS-binding protein (LBP) (18,40). With the detection of TLR4 as the transmembrane LPS signal conduit, CD14 was recognized as an important and necessary co-receptor with high specificity for LPS (41). Additionally, a soluble protein called myeloid-derived factor-2 (MD-2) which associate with the extracellular domain of TLR4, was detected and shown to be important in LPS induced TLR4 signalling (42).…”

“…It is, however, revealed that CD14 is essential for proper recognition of smooth LPS, the commonest form of LPS expressed by Gram-negative bacteria, but not rough LPS (47). CD14 is thereby thought to be a highly specific receptor and responsible for at least part of the ligand specificity of the LPS-receptor complex (41). CD14 has thus been named "the smooth operator" for LPS reponses (48).…”

Increased expression and internalization of the endotoxin coreceptor CD14 in enterocytes occur as an early event in the development of experimental necrotizing enterocolitis

“…Although the exact nature of interaction between these molecules is not known, it is thought that LPS can be shuttled to MD2 by CD14, allowing for a direct interaction between LPS-bound MD2 and TLR4 (12,13). Whereas both CD14-dependent and CD14-indepent activation of TLR4 has been documented, it is unclear what role, if any CD14 may play in the development of experimental NEC (14)(15)(16).…”

Expression of Legionella pneumophila paralogous lipid A biosynthesis genes under different growth conditions

“…Wild-type BALB/c and BALB/c CD142/2 mice (Gangloff et al, 2005;Haziot et al, 1996) were 5-7 weeks old, grown without pain and distress, and euthanized by CO 2 inhalation, following protocols approved by the institutional ethical committee for animal experiments (Université de Reims Champagne Ardenne). The mice were injected with 3 ml 3 % (w/v) Brewer's thioglycollate broth (bioMérieux).…”