dibutyryl-cyclic-gmp and Chediak-Higashi-Syndrome

Beige mutant (bg/bg) mice with Chediak-Higashi syndrome (CHS) were much more sensitive to virulent Salmonella enteritidis No. 11 strain than parental C57 BL/6 (+/+) or heterozygous (bg/+) mice, and they had weaker bactericidal activity against the organisms. Muramyl dipeptide (MDP) and N alpha-(N-acetyl-muramyl-L-alanyl-D-isoglutamyl)-N epsilon-stearoyl-L-lysine [MDP-Lys(L18)], a synthetic derivative of MDP, failed to confer any protection against the infection, but the MDPs showed some ability to stimulate the bactericidal activity in the peritoneal cavities and spleens of these mice. The bactericidal effect of MDP-Lys(L18) was dose-dependent, and the greatest effect was seen when it had been injected 24 hr before the infection. Multiple injections of MDP were much more beneficial than a single injection. Previous injection of N2,O2'-dibutyryl guanosine 3' : 5'-cyclic monophosphate (DB-cGMP) improved the impaired bactericidal capacity in beige mice, but the simultaneous injection of N6,O2-dibutyryl adenosine 3' : 5'-cyclic monophosphate (DB-cAMP) with DB-cGMP abolished the effect of DB-cGMP. The augmentation of bactericidal capacity by MDP-Lys(L18) was not affected by the injection of either DB-cGMP or DB-cAMP, suggesting that the effect of the MDPs was not related directly to cyclic nucleotide regulation in beige mice.

Topics: Acetylmuramyl-Alanyl-Isoglutamine; Animals; Bucladesine; Chediak-Higashi Syndrome; Dibutyryl Cyclic GMP; Mice; Mice, Mutant Strains; Salmonella enteritidis; Salmonella Infections

Topics: Adult; Atropine; Bucladesine; Carbachol; Cell Line; Cell Survival; Chediak-Higashi Syndrome; Cyclic GMP; Cytotoxicity, Immunologic; Dibutyryl Cyclic GMP; Humans; Immunity, Cellular; Incubators; Kinetics; Lymphocytes; Male

Polymorphonuclear leukocytes from humans and mice with the Chediak-Higashi syndrome were characterized by spin label electron spin resonance spectrometry. Our results suggest that cells from afflicted mice and humans have membranes more fluid than controls. Order parameters for a spin label that probes near the membrane surface were 0.652 for normals and 0.645 for two Chediak-Higashi patients. Cells from Chediak-Higashi mice showed similar differences, as did isolated plasma membrane fractions. An increased membrane fluidity was also detected with a spin label that probes deeper in the bilayer. In vitro treatment of Chediak-Higashi mouse cells with 0.01 M ascorbate increased the order parameter to normal levels. In vitro incubation of mouse Chediak-Higashi cells with glucose oxidase increased the order parameter, similar to the effect of ascorbate. This increase was abolished when catalase was added to the incubation medium. In vitro incubation with dibutyryl cyclic guanosine monophosphate (1 muM to 0.1 mM) did not normalize order parameters. These results indicate that fluidity of Chediak-Higashi cell membranes was affected by treatments expected to alter the oxidation: reduction potential of the environment but was not affected by treatments expected to alter the ratio of intracellular cyclic nucleotides. The latter treatment would affect microtubule assembly. Therefore, it appears that the membrane fluidity abnormalities as demonstrated by electron spin resonance and the earlier demonstrated microtubule dysfunctions characteristic of Chediak-Higashi cells are coexisting defects and are probably not directly related.

Topics: Animals; Ascorbic Acid; Cell Membrane; Chediak-Higashi Syndrome; Dibutyryl Cyclic GMP; Electron Spin Resonance Spectroscopy; Female; Glucose Oxidase; Humans; Hydrogen Peroxide; In Vitro Techniques; Membrane Fluidity; Methods; Mice; Neutrophils