The Journal of Immunology, Vol 153, Issue 1 287-299, Copyright © 1994 by American Association of Immunologists

ARTICLES

Discordant adaptation of human peritoneal macrophages to stimulation by lipopolysaccharide and the synthetic lipid A analogue SDZ MRL 953. Down- regulation of TNF-alpha and IL-6 is paralleled by an up-regulation of IL-1 beta and granulocyte colony-stimulating factor expression

HP Knopf, F Otto, R Engelhardt, MA Freudenberg, C Galanos, F Herrmann and RR Schumann
Department of Internal Medicine I, Freiburg University Medical Center, Germany.

Human peritoneal macrophages were exposed to increasing doses of LPS or a synthetic lipid A analogue (SDZ MRL 953) and production of the cytokines IL-1 beta, IL-6, TNF-alpha, and G-CSF was assessed at the protein and mRNA level. Cells were also prestimulated with low doses of LPS and SDZ MRL 953 to study their adaptation to a secondary challenge with high doses of LPS. The ability of macrophages to produce high levels of TNF-alpha and IL-6 after stimulation with LPS could be relieved almost completely by preincubating cells with low doses of LPS. Decreases of TNF-alpha and IL-6 production resulted from inhibition of gene transcription and/or changes in mRNA stability, as transcript levels of these cytokines were down-modulated by the process of LPS adaptation. Surprisingly, however, adapted cells were able to synthesize even larger quantities of G-CSF and IL-1 beta when exposed to a secondary LPS challenge. mRNA levels of the adapted cells remained unaltered for IL-1 beta, but were slightly increased for G-CSF as assessed by Northern blot analysis. High doses of the synthetic lipid A analogue SDZ MRL 953 were also able to adapt macrophages to a secondary LPS challenge by down-regulating TNF-alpha and IL-6 production, whereas priming secretion of G-CSF and IL-1 beta as well. We describe here the discordant adaptation of human peritoneal macrophages to a secondary LPS stimulus in vitro. These findings appear to have ramifications for the in vivo endotoxin response during inflammation and also Gram- negative septicemia.

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