Cytokine down-regulation in endotoxin tolerance.

Cytokine production is down-regulated in LPS tolerance. 1) This down-regulation has been reported in various animal species and cell types, and can be induced both in vivo and in vitro (indicating a desensitization of the cytokine-producing cells). 2) It can also be induced in humans in vivo and in vitro. 3) It is reversible, since the refractory state can be bypassed by administering LPS along with IFN-gamma or PMA. 4) Under certain conditions, it is specific since cytokines will still be induced in response to non-LPS stimuli (Staphylococcus, zymosan, MDP), meaning a real LPS-desensitization is involved rather than an aspecific blockade of cytokine synthesis. 5) in vivo, due to the complexity of the system, other factors than a simple desensitization of cytokine-producing cells contribute to LPS tolerance (aspecific blockade of cytokine synthesis, corticosteroid-dependent feedback, increased clearance by RES and changes in macrophage populations, inhibitory cytokines.