The role of bacterial LPS is to trigger agood enough innate immune system in mammalian hosts.
The lipid moiety, lipid A, is regarded to beendotoxic and is important to the endotoxin activity of LPS. Additionally, itis a bioactive element of LPS and is recognised by the innate immune systemeven when present at low levels. Immune detection of lipid A is highlysensitive and potent that even a bloodstream infection can cause endotoxicshock. LPS stimulates an immune response by interacting with some of the activereceptors – cluster of differentiation14 (CD14) and lymphocyte antigen 96 (MD2) receptor complex, all of which havebeen found to trigger the production of pro-inflammatory cytokines such astumour necrosis factor-? (TNF), interleukin-6 (IL-6) and interleukin-1 (IL-1).
LPS can also bind to Toll receptors, whichare intracellular signalling domain, and LPS signalling has also beenspecifically linked to Toll-like receptor 4 (TLR4). LPS activates proximalsignalling pathways in a similar way to those used by IL-1, IL-1receptor-associated kinase (IRAK) and TNFR-associated factor 6 (TRAF 6).Moreover, LPS exposure has been associated with the activation of a number ofsignalling cascades, hence stimulating the secretion of inflammatory mediators.LPS are recognised by their host cells because TLR4 and myeloid differentiationfactor 2 (MD-2) form a heterodimer, and are able to pick out certain commoncharacteristics in structurally diverse LPS molecules. Determining the crystalstructure of the TLR4-MD-2-LPS complex helps to simplify their ligandspecificity and receptor activation mechanism.
Two copies of the TLR4-MD-2-LPScomplex are arranged symmetrically and this comes about from the formation ofan m-shaped receptor multimer resulting from LPS binding. LPS interacts with a largehydrophobic pocket in MD-2, with one of the six lipid chains of LPS forming ahydrophobic interaction with the conserved phenylalanines of TLR4.