Glycosphingolipids (GSL) isolated from the gram-negative lipopolysaccharide (LPS)-free bacterium Sphingomonas paucimobilis have remarkable structural similarities with LPS and its hydrophobic part, termed lipid A. Like LPS, but in contrast to the structurally related ceramides and cerebrosides, GSL contain an alpha-linked, negatively charged pyranosidic glycosyl component adjacent to the lipid portion and are capable of forming membranes. Because of these similarities, it was of interest to investigate whether these GSL are also able to induce monokine production in human mononuclear cells (MNC). Our results show that a GSL containing four sugar residues (GSL-4A) induced the release of tumor necrosis factor, interleukin-6, and interleukin-1 in MNC, whereas GSL-1, containing only one glycosyl residue, was inactive. A minimal concentration of 1 microgram of GSL-4A per ml was necessary to induce monokine production in MNC, whereas LPS was as active at a 10,000-fold-lower concentration (0.1 ng/ml). Both GSL-4A-induced monokine production and LPS-induced monokine production were reduced by the bactericidal/permeability-increasing protein and GSL-1. In contrast to LPS, GSL-4A-induced monokine release could be inhibited neither by an anti-CD14 monoclonal antibody nor by lipid A partial structures. We therefore conclude that at the receptor level, different mechanisms are involved in the LPS- and GSL-4A-induced monokine release
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