Induction of tumor necrosis factor-alpha release by lipopolysaccharide and defined lipopolysaccharide partial structures

Abstract

We have investigated the release of tumor necrosis factor-alpha (TNF-alpha) by human mononuclear cells (MNC) and isolated human monocytes/macrophages stimulated with S- and R-form lipopolysaccharide (LPS), natural lipid A, and natural and synthetic partial structures thereof. We found that LPS of Salmonella minnesota (S. min.) Rb2, which represents a partial structure of wildtype LPS of Salmonella abortus equi (S.a.e.) lacking the O-chain and parts of the outer core region, was the most active inducer of all substances tested, even more active than the wildtype LPS. Lipid A also induced the production of TNF-alpha by monocytes/macrophages but was less active than wildtype LPS. The natural Escherichia coli (E. coli) type hexaacyl lipid A (compound 506) was more active than the natural S. min. type heptaacyl lipid A (compound 516). The 1- and 4'-monodephospho partial structures (compounds 505 and 504) of E. coli lipid A were less active and represented the smallest structures tested that were able to induce TNF-alpha release by monocytes/macrophages. Synthetic tetraacyl lipid A precursor Ia of E. coli lipid A, lacking non-hydroxylated fatty acids (compound 406), and the monosaccharide precursor lipid X did not induce the release of TNF-alpha in MNC or isolated monocytes/macrophages. This might indicate that the ability of a lipid A structure to induce the release of TNF-alpha is closely connected with the conditions to be at least hexaacylated and/or to contain hydroxylated fatty acids. These results demonstrate a structure-dependent hierarchy of LPS and natural or synthetic partial structures in their capacity of inducing TNF-alpha release by monocytes/macrophages.