LACK OF CROSS-TOLERANCE BETWEEN LPS AND MURAMYL DIPEPTIDE IN INDUCTION OF CIRCULATING TNF-ALPHA AND IL-6 IN GUINEA-PIGS

In guinea pigs, Lipopolysaccharide (LPS) from gram-negative bacteria a nd muramyl dipeptide (MDP) from gram-positive bacteria are potent indu cers of systemic production of proinflammatory cytokines and fever. Ho wever, there is a striking difference between these two bacterial pyro gens in so far as repeated administration of LPS, but not of MDP, in s hort-term intervals induces tolerance by a progressive downregulation of the systemic cytokine network. In the present study, we investigate d MDP-induced fever and the systemic release of tumor necrosis factor- alpha (TNF-alpha) and interleukin-6 (IL-6) in LPS-tolerant guinea pigs in comparison with naive animals. Endotoxin tolerance was induced by repeated intramuscular injections of 20 mu g/kg LPS at intervals of 3 days. In response to the last of five injections with LPS, systemic pr oduction of TNF-alpha and IL-6 as well as the development of a febrile response was abrogated almost completely. Those guinea pigs that had developed an LPS tolerance could, however, produce the same amounts of TNF-alpha and IL-6 as naive animals in response to a challenge with M DP. Also, MDP-induced fever was identical in LPS-tolerant and naive gu inea pigs. These results provide evidence for a lack of cross toleranc e between LPS and MDP in induction of circulating cytokines and fever in guinea pigs.