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-α) 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.) Rb 2, which represents a partial structure of wildtype LPS of Salmonella abortus equi (S.a.e.) lacking the 0-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-α 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-α release by monocytes/macrophages. Synthetic tetraacyl lipid A precursor la 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-α in MNC or isolated monocytes/macrophages.This might indicate that the ability of a lipid A structure to induce the release of TNF-α 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-α release by mono cytes/macrophages.