Differential desensitization of lipopolysaccharide-inducible chemokine gene expression in human monocytes and macrophages

Bacterial lipopolysaccharide (LPS) has been shown to induce a wide variety of proinflammatory cytokines and chemokines. An initial challenge with minu te amounts of LPS causes tolerance to later LPS effects which is characteri zed by a much lower or abrogated release of pro-inflammatory cytokines. To explore the relationship between the production of chemokines and the induc tion of LPS tolerance, we pretreated human monocytes with increasing LPS do ses and thereafter restimulated with LPS. The re-expression of the CC chemo kines macrophage inflammatory protein (MIP)-1 alpha, MIP-1 beta and RANTES was substantially suppressed after pre-incubation with low LPS doses. In st riking contrast, the reexpression of neutrophil-attracting IL-8 and melanom a growth stimulatory activity-alpha and of the monocyte-attracting monocyte chemotactic protein-1 remained high and was, in part, initially increased after restimulation with LPS. The corresponding gene expression pattern as determined by Northern blot analyses correlated closely with the release of chemokines and cytokines. Thus, a basic set of chemotactic mediators that are still produced by otherwise LPS-desensitized monocytes/macrophages may ensure the continuing recruitment of monocytes and neutrophils into an infl ammatory process caused by gram-negative bacteria.