DISCORDANT ADAPTATION OF HUMAN PERITONEAL-MACROPHAGES TO STIMULATION BY LIPOPOLYSACCHARIDE AND THE SYNTHETIC LIPID-A ANALOG SDZ-MRL-953 - DOWN-REGULATION OF TNF-ALPHA AND IL-6 IS PARALLELED BY AN UP-REGULATIONOF IL-1-BETA AND GRANULOCYTE-COLONY-STIMULATING FACTOR EXPRESSION

Human peritoneal macrophages were exposed to increasing doses of LPS o r a synthetic lipid A analogue (SDZ MRL 953) and production of the cyt okines IL-1 beta, IL-6, TNF-alpha, and G-CSF was assessed at the prote in and mRNA level. Cells were also prestimulated with low doses of LPS and SDZ MRL 953 to study their adaptation to a secondary challenge wi th high doses of LPS. The ability of macrophages to produce high level s of TNF-alpha and IL-6 after stimulation with LPS could be relieved a lmost completely by preincubating cells with low doses of LPS. Decreas es of TNF-alpha and IL-6 production resulted from inhibition of gene t ranscription 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 lar ger 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 95 3 were also able to adapt macrophages to a secondary LPS challenge by down-regulating TNF-alpha and IL-6 production, whereas priming secreti on of G-CSF and IL-1 beta as well. We describe here the discordant ada ptation of human peritoneal macrophages to a secondary LPS stimulus in vitro. These findings appear to have ramifications for the in vivo en dotoxin response during inflammation and also Gram-negative septicemia .