Inhibition of lipopolysaccharide-induced macrophage tumor necrosis factor-α synthesis by polymyxin B sulfate

C. P. Coyne From the Departments of Clinical Science (Coyne), and Pathology (Fenwick), College of Veterinary Medicine, Kansas State University, Manhattan. KS 66502.

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Brad W. Fenivick From the Departments of Clinical Science (Coyne), and Pathology (Fenwick), College of Veterinary Medicine, Kansas State University, Manhattan. KS 66502.

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SUMMARY

The antibiotic polymyxin B sulfate is a cationic polypeptide with a unique cyclical configuration and distinct cationic characteristics. In this investigation, polymyxin H was evaluated to determine its ability to prevent synthesis of lactic acid and tumor necrosis factor-α (tnf-α) by lipopolysaccharide-stimulated strain RAW 264.7 macrophage-like cell populations. In this context, gradient concentrations of polymyxin B were formulated in the presence of fixed concentrations of lipopolysaccharide fractions from Escherichia coli (B4:0111), E coli (J5), Klebsiella pneumoniae, Pseudomonas aeruginosa. Salmonella minnesota, and S typhimurium (Re). Quantitation of tnf-α was established by the application of a tissue culture-based biological assay system, using the WEHI 164 clone 13 indicator cell line. Investigations also included evaluation of the ability of gradient concentrations of lipopolysaccharide fractions from E coli (B4:0111), E coli Q5), K pneumoniae, P aeruginosa, S minnesota, and S typbimurium (Re) to form a complex with polymyxin B. This was established through application of high-performance thin-layer chromatography techniques. On the basis of the known molecular characteristics of lipopolysaccharide, its lipid A-core subfractions, and polymyxin B, these results imply that cytoprotective properties of polymyxin B are attributable to direct interaction and subsequent complex formation. More specifically, the mechanism by which polymyxin B exerts affinity for lipopolysaccharide fractions is proposed to occur through attractive ionic interactions established between the cationic diami-nobutyric acid residues of polymyxin B and the mono- or diphosphate group(s) of the lipid A-corc moiety. It is highly probable that this molecular phenomenon is accompanied by hydrophobic interactions established between the terminal methyloctanoyl or methylheptanoyl groups of polymyxin B and the saturated carbon chains of the lipid A-core subfraction of lipopolysaccharide fractions

SUMMARY

The antibiotic polymyxin B sulfate is a cationic polypeptide with a unique cyclical configuration and distinct cationic characteristics. In this investigation, polymyxin H was evaluated to determine its ability to prevent synthesis of lactic acid and tumor necrosis factor-α (tnf-α) by lipopolysaccharide-stimulated strain RAW 264.7 macrophage-like cell populations. In this context, gradient concentrations of polymyxin B were formulated in the presence of fixed concentrations of lipopolysaccharide fractions from Escherichia coli (B4:0111), E coli (J5), Klebsiella pneumoniae, Pseudomonas aeruginosa. Salmonella minnesota, and S typhimurium (Re). Quantitation of tnf-α was established by the application of a tissue culture-based biological assay system, using the WEHI 164 clone 13 indicator cell line. Investigations also included evaluation of the ability of gradient concentrations of lipopolysaccharide fractions from E coli (B4:0111), E coli Q5), K pneumoniae, P aeruginosa, S minnesota, and S typbimurium (Re) to form a complex with polymyxin B. This was established through application of high-performance thin-layer chromatography techniques. On the basis of the known molecular characteristics of lipopolysaccharide, its lipid A-core subfractions, and polymyxin B, these results imply that cytoprotective properties of polymyxin B are attributable to direct interaction and subsequent complex formation. More specifically, the mechanism by which polymyxin B exerts affinity for lipopolysaccharide fractions is proposed to occur through attractive ionic interactions established between the cationic diami-nobutyric acid residues of polymyxin B and the mono- or diphosphate group(s) of the lipid A-corc moiety. It is highly probable that this molecular phenomenon is accompanied by hydrophobic interactions established between the terminal methyloctanoyl or methylheptanoyl groups of polymyxin B and the saturated carbon chains of the lipid A-core subfraction of lipopolysaccharide fractions

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