EARLY DOWN-REGULATION OF TNF PRODUCTION BY LPS TOLERANCE IN HUMAN MONOCYTES - COMPARISON WITH IL-1-BETA, IL-6, AND IL-8

We studied the effect of a 4-hr preexposure to LPS on the ability of h uman monocytes to respond to a subsequent stimulation with LPS in term s of cytokine production. LPS-preexposed monocytes did not produce TNF on LPS restimulation, but they retained the ability to produce IL-1be ta, IL-6, and IL-8. LPS-tolerant monocytes were still capable of produ cing TNF when restimulated with zymosan. Down-regulation of TNF by LPS tolerance was also evident at the mRNA level. To investigate the poss ible mechanisms underlying this phenomenon, we also studied the effect of LPS preexposure on membrane CD14, which was suggested to be an LPS receptor, and on intracellular cAMP, an inhibitor of TNF production. LPS induced a 50% decrease in CD14 expression. On the other hand, the increase in cAMP levels by LPS was not affected by preexposure to LPS. In conclusion, (a) TNF is more rapidly down-regulated than IL-1beta, IL-6, and IL-8 during LPS tolerance in vitro; (b) early LPS tolerance is associated with decreased CD14, which might partially explain the d ecreased LPS response; and (c) a feedback mechanism controlling TNF sy nthesis, cAMP elevation, is not down-regulated in LPS tolerance.