Bacterial lipopolysaccharides and innate immunity

Bacterial lipopolysaccharides (LPS) are the major outer surface membrane co mponents present in almost all Gram-negative bacteria and act as extremely strong stimulators of innate or natural immunity in diverse eukaryotic spec ies ranging from insects to humans. LPS consist of a poly- or oligosacchari de region that is anchored in the outer bacterial membrane by a specific ca rbohydrate lipid moiety termed lipid A. The lipid A component is the primar y immunostimulatory centre of LPS. With respect to immunoactivation in mamm alian systems, the classical group of strongly agonistic (highly endotoxic) forms of LPS has been shown to be comprised of a rather similar set of lip id A types. In addition, several natural or derivatised lipid A structures have been identified that display comparatively low or even no immunostimul ation for a given mammalian species. Some members of the latter more hetero geneous group are capable of antagonizing the effects of strongly stimulato ry LPS/lipid A forms. Agonistic forms of LPS or lipid A trigger numerous ph ysiological immunostimulatory effects in mammalian organisms, but - in high er doses - can also lead to pathological reactions such as the induction of septic shock. Cells of the myeloid lineage have been shown to be the prima ry cellular sensors for LPS in the mammalian immune system. During the past decade, enormous progress has been obtained in the elucidation of the cent ral LPS/lipid A recognition and signaling system in mammalian phagocytes. A ccording to the current model, the specific cellular recognition of agonist ic LPS/lipid A is initialized by the combined extracellular actions of LPS binding protein (LBP), the membrane-bound or soluble forms of CD14 and the newly identified Toll-like receptor 4 (TLR4)*MD-2 complex, leading to the r apid activation of an intracellular signaling network that is highly homolo gous to the signaling systems of IL-1 and IL-18. The elucidation of structu re-activity correlations in LPS and lipid A has not only contributed to a m olecular understanding of both immunostimulatory and toxic septic processes , but has also re-animated the development of new pharmacological and immun ostimulatory strategies for the prevention and therapy of infectious and ma lignant diseases.