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Am J Physiol Regul Integr Comp Physiol 273: R1529-R1533, 1997;
0363-6119/97 $5.00
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AJP - Regulatory, Integrative and Comparative Physiology, Vol 273, Issue 4 1529-R1533, Copyright © 1997 by American Physiological Society

ARTICLES

Lack of cross tolerance between LPS and muramyl dipeptide in induction of circulating TNF-alpha and IL-6 in guinea pigs

J. Roth, T. Aslan, B. Storr and E. Zeisberger
Physiologisches Institut, Klinikum der Justus-Liebig-Universitat, Giessen, Germany.

In guinea pigs, lipopolysaccharide (LPS) from gram-negative bacteria and muramyl dipeptide (MDP) from gram-positive bacteria are potent inducers of systemic production of proinflammatory cytokines and fever. However, there is a striking difference between these two bacterial pyrogens in so far as repeated administration of LPS, but not of MDP, in short-term intervals induces tolerance by a progressive downregulation of the systemic cytokine network. In the present study, we investigated 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 microg/kg LPS at intervals of 3 days. In response to the last of five injections with LPS, systemic production 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 MDP. Also, MDP-induced fever was identical in LPS-tolerant and naive guinea pigs. These results provide evidence for a lack of cross tolerance between LPS and MDP in induction of circulating cytokines and fever in guinea pigs.


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