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The Journal of Immunology, Vol 153, Issue 11 5230-5238, Copyright © 1994 by American Association of Immunologists

ARTICLES

Acyclic analogue of lipid A stimulates TNF-alpha and arachidonate release via a unique LPS-signaling pathway

MA Fagan, Y Liu, P Stutz, H Vyplel and DT Golenbock
Department of Internal Medicine, Maxwell Finland Laboratory for Infectious Diseases, Boston City Hospital, Boston University School of Medicine, MA 02118.

LPS has been implicated in the pathogenesis of Gram-negative bacterial sepsis. Despite intensive efforts to define the LPS-signal transduction pathway, CD14 is the sole molecule clearly demonstrated to possess signaling capabilities. However, it remains unclear whether CD14 is the only LPS-signaling molecule expressed in phagocytes and how CD14- mediated signaling occurs. Compound SDZ 280.961 is a synthetic triacylated amino acid that structurally resembles the reducing sugar moiety of lipid A. SDZ 280.961 effectively stimulated TNF-alpha release from human PBMC. Co-incubation of PBMC with the specific LPS inhibitor Rhodobacter sphaeroides lipid A inhibited SDZ 280.961-mediated stimulation of TNF-alpha release, indicating that this analogue signals mononuclear cells via a LPS-activated signaling pathway. Induction of TNF-alpha release from mononuclear cells by SDZ 280.961 was strongly dependent on the presence of serum and was enabled by the presence of purified LPS-binding protein, characteristics of CD14-mediated signaling. In contrast, SDZ 280.961-mediated signaling was not inhibited by blocking anti-CD14 mAbs. A Chinese hamster ovary fibroblast line transfected with human CD14, which responds to LPS in a manner qualitatively similar to that of macrophage cell lines, failed to respond to SDZ 280.961. Taken together, these data suggest that the lipid A analogue SDZ 280.961 activates monocytes via a unique LPS- signal transduction pathway that appears to be independent of CD14.


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