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.
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.
Knopf
H P
HP
Department of Internal Medicine I, Freiburg University Medical Center, Germany.
Otto
F
F
Engelhardt
R
R
Freudenberg
M A
MA
Galanos
C
C
Herrmann
F
F
Schumann
R R
RR
D015232:Dinoprostone / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D016179:Granulocyte Colony-Stimulating Factor / Q000378:metabolism*; D006801:Humans; D007375:Interleukin-1 / Q000378:metabolism*; D015850:Interleukin-6 / Q000378:metabolism*; D008050:Lipid A / Q000031:analogs & derivatives* / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology*; D017737:Macrophages, Peritoneal / Q000187:drug effects* / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D018805:Sepsis / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D007375:Interleukin-1; D015850:Interleukin-6; D008050:Lipid A; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; C068979:SDZ MRL 953; D016179:Granulocyte Colony-Stimulating Factor; D015232:Dinoprostone