Endotoxic induction of prostaglandin release from macrophages by nontoxic lipid A analogs synthesized chemically

Abstract

The ability of synthetic lipid A analogs to induce prostaglandin synthesis in macrophages was compared with that of native lipopolysaccharide. The synthetic preparations comprised monomeric or dimeric derivatives of D-glucosamine with different patterns of substitution by phosphate and tetradecanoic, (R)-3-hydroxytetradecanoic, and (R)-3-tetradecanoyloxytetradecanoic acid. All of these preparations are structurally distinct from native lipid A (principally regarding the position of fatty acid substitution) and hence have been previously shown to be endotoxically inactive in many biological tests. It was found that many of these synthetic samples exhibit strong activity in inducing prostaglandin E2 and prostaglandin F2 alpha, with some of them having activity comparable to that of lipopolysaccharide. Experiments with macrophages of C3H/HeJ mice enabled us to differentiate between endotoxin-specific (in the case of dimeric preparations) and endotoxin-nonspecific (for monomeric preparations) mechanisms for the induction of prostaglandins. These results indicate that there is a difference in the mechanism of induction of prostaglandin synthesis between monomeric lipid A's and dimeric or native lipid A structures.

Free hydroxyl groups are not required for endotoxic activity of lipid A

“…The number and the position of the substituted fatty acids are also important to its activities. Overacylation of hydroxyl groups in lipid A decreases its activities, as shown for Salmonella lipid A (3,7,8,16,19,20).…”

Differing signal requirements for the activation of macrophages from C3H/HeJ and C3H/OuJ mice

“…The activation of macrophages reflects a variety of responses, depending on the stimulus and the signal(s) triggered by stimulation [1,2]. Endotoxin is a potent macrophage activator [3] and it is believed that the various effects of endotoxin are due, in part, to cytokines produced by activated macrophages [4]. These cytokines include: interleukin-1 (IL-1), tumor necrosis factor (TNF), and the products of arachidonic acid metabolism [3,5,6].…”

Dissociation of endotoxic activities in a chemically synthesized lipid A precursor after acetylation

“…After the chemical structure of lipid A from Escherichia coli was established with the help of chemically synthesized compounds, which were revealed to exhibit biological activities identical to that of native lipid A (2,3), an attempt was made to clarify the relationship between the chemical structure of lipid A and its biological activities, with the aim of dissociating the beneficial activity of lipid A from its toxicity. However, the accumulated data indicated that this would be very difficult (1,4,5,10,12,13). Endotoxic activity is divided into three categories: reaction in the whole body, cellular response, and reaction at the molecular level, represented by Limulus amoebocyte lysate (LAL) gelation.…”