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

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Abstract
Bacterial lipopolysaccharide (LPS) has been shown to induce a wide variety of pro-inflammatory cytokines and chemokines. An initial challenge with minute amounts of LPS causes tolerance to later LPS effects which is characterized by a much lower or abrogated release of pro-inflammatory cytokines. To explore the relationship between the production of chemokines and the induction of LPS tolerance, we pretreated human monocytes with increasing LPS doses and thereafter restimulated with LPS. The re-expression of the CC chemokines macrophage inflammatory protein (MIP)-1α, MIP-1β and RANTES was substantially suppressed after pre-incubation with low LPS doses. In striking contrast, the re-expression of neutrophil-attracting IL-8 and melanoma growth stimulatory activity-α 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 inflammatory process caused by gram-negative bacteria.

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