Enzymatically deacylated Neisseria lipopolysaccharide (LPS) inhibits murine splenocyte mitogenesis induced by LPS

Abstract

Acyloxyacyl hydrolase is a leukocyte enzyme that selectively removes the secondary acyl chains from the lipid A moiety of gram-negative bacterial lipopolysaccharides (LPS). As predicted by the reported contribution of secondary acyl chains to the bioactivities of lipid A analogs, enzymatic deacylation of Salmonella typhimurium Rc LPS substantially reduces its potency in the dermal Shwartzman reaction and in several in vitro assays that measure responses of human endothelial cells and neutrophils, whereas the potency of this LPS for inducing murine splenocyte mitogenesis is affected much less. In the experiments described here, we studied the impact of acyloxyacyl hydrolysis on the bioactivities of several LPS that differ from Salmonella LPS in carbohydrate and lipid A structures. Deacylated LPS from Escherichia coli, Haemophilus influenzae, Neisseria meningitidis, and S. typhimurium were similarly reduced in potency in the Limulus lysate test (30to 60-fold reduction in potency relative to the corresponding mock-treated LPS), and the ability of all of these deacylated LPS to stimulate neutrophil adherence to human endothelial cells was reduced by a factor of 100 or more. For LPS from E. coli, H. influenzae, and Pseudomonas aeruginosa, the impact of deacylation on spleen cell mitogenesis was also similar to that observed for S. typhimurium LPS: deacylation reduced potency by less than 15-fold. Unexpectedly, the potency of Neisseria LPS in the murine splenocyte mitogenicity test was reduced over 100-fold by deacylation, and deacylated Neisseria LPS could block the mitogenic activity of Neisseria and Salmonella LPS. These studies indicate that the contribution of secondary acyl chains to the bioactivities of a given LPS cannot be predicted with confidence from the reported structure-activity relationships of lipid A or from the behavior of other deacylated LPS.

Endotoxin activates human vascular smooth muscle cells despite lack of expression of CD14 mRNA or endogenous membrane CD14

“…Synthetic lipid A precursor Ia (36) or nontoxic LPSs (43) specifically inhibit LPS-induced production of cytokines in monocytes. Besides cytokine production (12,13,29), LPS antagonists also block other endotoxin-induced activities (11,17,27,45,54,59). These data indicated specific recognition of LPS by the target cells.…”

The Expression Profile of Lipopolysaccharide‐Binding Protein, Membrane‐Bound CD14, and Toll‐Like Receptors 2 and 4 in Chronic Periodontitis

“…24,25 Therefore, LBP plays a central role in mediating cellular responses to LPS. 26 Extensive evidence shows that LPS is an important etiologic factor in the pathogenesis of periodontitis. 27 It has been reported that the local concentrations of LBP and CD14 in gingival tissues and gingival crevice may be the arbiters for the immunobiological effects of LPS in the periodontal diseases.…”

Suppression of C3H/HeJ cell activation by lipopolysaccharide endotoxin

“…However, lipid A-associated protein activation of these cells was not inhibited, and optimal inhibition was observed when the inhibitors were added prior to the mitogens, suggesting competitive inhibition of a putative lipid A receptor (16). More recently, Erwin et al (3) reported that a nonmitogenic deacylated Neisseria meningitidis LPS blocked the mitogenic activity of Salmonella LPS in normal responder C3H/HeN spleen cells; however, this inhibition was also LPS specific and not observed with ConA-stimulated spleen cells. In our hands, the most efficient inhibitor has been the complete wild-type smooth LPS.…”