LIPOPOLYSACCHARIDE-DEPENDENT AND LIPOPOLYSACCHARIDE-INDEPENDENT PATHWAYS OF MONOCYTE DESENSITIZATION TO LIPOPOLYSACCHARIDES

The present study demonstrates that with time in culture blood monocytes (MO) lose their ability to express procoagulant activity (PCA) and secrete tumor necrosis factor-alpha (TNF-alpha) in culture medium in response to lipopolysaccharide (LPS) stimulation. Thus, upon 10-mu-g/ml LPS stimulation for 4 hours 2-day-old MO produced lower levels of PCA and TNF-alpha than fresh MO. The decrease in responsiveness was not caused by cell death, since in the case of TNF-alpha it was fully reversible by interferon-gamma (IFN-gamma). Compared with cells pre-incubated in medium alone, the responsiveness of MO pre-incubated in LPS was further decreased. Thus, in MO LPS pre-incubation was followed by an LPS refractory state. It was expected that the decrease in responsiveness induced by cultivation in medium alone was mediated by LPS contamination of culture medium. However, as we were unable to prevent this decrease by neutralizing LPS contamination of the culture medium with polymyxin B, the loss in LPS-induced activities of cultured MO is likely to be mediated by culture conditions other than LPS contamination. Taken together the present data demonstrate that LPS-dependent as well as LPS-independent pathways of MO desensitization to LPS exist.