[The role of cytokines in endotoxic shock and in endotoxin hypersensitivity]

Endotoxins (lipopolysaccharides, LPS) are constituents of the outer membrane of gram-negative bacteria. The application of purified LPS to experimental animals leads to the development of many pathophysiological activities which are also seen during infection with gram-negative microorganisms. One important prerequisite for the development of endotoxin shock is the interaction of LPS with macrophages, the activation of which leads to the release of cytokines, in particular of TNF alpha and IL-1, which mediate the toxic activity of LPS. The interaction of LPS with target cells and the subsequent initiation of endotoxin shock may be modified by plasma proteins that are capable of binding LPS. The most important LPS-binding proteins known so far are high density lipoprotein (HDL), low density lipoprotein (LDL), LPS-binding protein (LBP) and specific LPS antibodies. Native LPS released from bacteria may be associated partly with bacterial proteins (e.g. OmpA) which may also modify its interaction with host targets. The sensitivity of the organism to LPS is genetically determined, but may be altered under different experimental conditions. Hypersensitivity to LPS may be achieved by treatment with live (infection) or killed microorganisms, growing tumors, hepatotoxic agents or treatment with proteins to which the organism has been immunologically primed. The state of hypersensitivity is characterized by an increased ability of hypersensitive animals to produce cytokines on LPS challenge, as well as by an increased susceptibility to the toxic activity of TNF alpha. Recently it could be shown that interferon gamma (IFN gamma) is a central mediator in the development of the hypersensitivity to LPS induced by infection.