Inhibition of in vitro differentiation of human monocytes to macrophages by lipopolysaccharides (LPS): phenotypic and functional analysis

Brugger, W. ; Reinhardt, D. ; Galanos, C. ; Andreesen, Reinhard

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Zusammenfassung

Zusammenfassung

Blood monocytes (MO) undergo maturation into macrophages (MAC) upon migration from the capillary bed to tissue sites of inflammation where they are exposed to environmental signals. Functional competence and phenotype heterogeneity is the result of both differentiation-inducing and -activating events. In vitro, MO to MAC maturation is induced by serum factors, can be followed by the expression of specific maturation-associated antigens and is accompanied by a characteristic change in the secretory repertoire of MAC in comparison to MO. Here we report that bacterial lipopolysaccharides (LPS) at subnanogram quantities very effectively inhibited the serum-induced maturation of human MO in vitro. At the same time LPS induced the up-regulation of CD14 antigens. The lipid A moiety was shown to be responsible for this novel biological activity of the LPS molecule. Inhibition of maturation was not due to secondary LPS-induced signals like interleukin (IL)-1, IL-6, tumor-necrosis factor (TNF)-alpha or interferon (IFN)-alpha--even though the latter by itself suppressed MAC maturation in vitro. The inhibitory activity of IFN-alpha could be abolished by neutralizing anti-IFN-alpha antibodies whereas these antibodies had no effect on LPS-induced suppression of MAC maturation. Functional analysis of LPS-treated MO long-term cultures showed that the pattern of secretory products released was similar to that of freshly-isolated immature blood MO: compared with mature MAC, LPS-treated MO released high amounts of IL-6 but significantly less TNF-alpha, neopterin, lysozyme and beta-2-microglobulin. At the same time, in LPS-treated MO cultures the MAC maturation-associated molecules alpha-2-macroglobulin and fibronectin could be detected only in trace amounts. The ability to secrete IL-1, however, was lost both in control as well as in LPS-treated MO cultures. The results indicate that endotoxins may influence the biology of the MO/MAC system distinctively: they not only induce a functional activation but also interfere with the ontogeny of this cell family.

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