THE ROLE OF CYTOKINES IN ENDOTOXIN-SHOCK AND ENDOTOXIN HYPERSENSITIVITY

Endotoxins (lipopolysaccharides, LPS) are constituents of the outer me mbrane of gram-negative bacteria. The application of purified LPS to e xperimental animals leads to the development of many pathophysiologica l activities which are also seen during infection with gram-negative m icroorganisms. One important prerequisite for the development of endot oxin shock is the interaction of LPS with macrophages, the activation of which leads to the release of cytokines, in particular of TNFalpha 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. T he most important LPS-binding proteins known so far are high density l ipoprotein (HDL), low density lipoprotein (LDL), LPS-binding protein ( LBP) and specific LPS antibodies. Native LPS released from bacteria ma y be associated partly with bacterial proteins (e.g. OmpA) which may a lso modify its interaction with host targets. The sensitivity of the o rganism to LPS is genetically determined, but may be altered under dif ferent experimental conditions. Hypersensitivity to LPS may be achieve d by treatment with live (infection) or killed microorganisms, growing tumors, hepatotoxic agents or treatment with proteins to which the or ganism 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 suscept ibility to the toxic activity of TNFalpha. Recently it could be shown that interferon gamma (IFNgamma) is a central mediator in the developm ent of the hypersensitivity to LPS induced by infection.