Alteration of Sphingolipid Metabolism in Leukocytes from Patients with the Chediak–Higashi Syndrome

Kanfer, Julian N.; Blume, R; Yankee, Ronald A.; Wolff, Sheldon M.

doi:10.1056/nejm196808222790806

Cited by 24 publications

(10 citation statements)

References 18 publications

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“…Decreased cholesterol content would be expected to give rise to increased membrane fluidity (17) such as we report here. An accelerated turnover of sphingolipids in CHS leukocytes has been demonstrated (22), and is consistent with previous reports of a decreased sphingolipid content in CHS PMN membrane (23) and in serum (21). This decrease, together with the reported concurrent increase in lecithin content (21), would be expected to give rise to increased membrane fluidity.…”

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confidence: 92%

Membrane Fluidity in Human and Mouse Chediak-Higashi Leukocytes

et al. 1979

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A B S T R A C T 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 memiibrane 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 ,uM 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 dysfunction s characteristic of Chediak-Higashi cells are coexistinig defects and are probably not directly related.

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confidence: 92%

Membrane Fluidity in Human and Mouse Chediak-Higashi Leukocytes

et al. 1979

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“…Cer, C 2 -ceramide; E, E-64-d; P, PMA. In leukocytes from CHS patients, SM hydrolysis is reported to be accelerated [14]. Because we showed that both N-SMase and A-SMase activity in unstimulated beige cells was higher than that in unstimulated normal cells, it is considered that the increased ceramide is produced from SM hydrolysis by the action of SMase.…”

Section: Discussionmentioning

confidence: 78%

“…Meanwhile, it was reported that sphingomyelin (SM) turnover is accelerated in leukocytes from CHS patients [14]. In addition, ceramide that is produced by sphingomyelinase (SMase) action has been known to play an important role in cell differentiation, cell proliferation, or the induction of apoptosis [15,16].…”

Section: Introductionmentioning

confidence: 99%

Abnormal down-regulation of PKC is responsible for giant granule formation in fibroblasts from CHS (beige) mice—a thiol proteinase inhibitor, E-64-d, prevents giant granule formation in beige fibroblasts

Tanabe¹,

Cui

Ito

2000

Journal of Leukocyte Biology

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We have previously reported that the abnormally rapid down-regulation of protein kinase C (PKC) activity is responsible for the cellular dysfunction in natural killer (NK) cells and polymorphonuclear leukocytes (PMNs) from ChediakHigashi syndrome (beige) mice. In this report, we examined whether the down-regulation of PKC is associated with giant granule formation in fibroblasts from beige mice. In cultured beige fibroblasts, the membrane-bound PKC activity declined significantly after phorbol ester stimulation. We found that E-64-d, which is a thiol proteinase inhibitor and protects PKC from calpain-mediated proteolysis, reversed the declined PKC activity and prevented giant granule formation in beige fibroblasts. Moreover, E-64-d corrected the reduced lysosomal elastase and cathepsin G activity in beige fibroblasts. In contrast, specific PKC inhibitors, chelerythrin and calphostin C, promoted giant granule formation in normal fibroblasts. We also demonstrate that ceramide production is enhanced in beige fibroblasts and is involved in the rapid down-regulation of PKC. These results suggest that the accelerated breakdown of PKC observed in beige fibroblasts is caused by enhanced ceramide production and is also responsible for giant granule formation. J. Leukoc. Biol. 67: 749-755; 2000.

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“…In the former instance, the fluidity change is secondary to increased levels of cholesterol in the serum (14) . Unusual lipid serum levels have been reported for CHS (25) as well as other lipid-related metabolic abnormalities (24,33) . With these considerations in mind, we elected to study erythrocytes from normal subjects as well as from those suffering from CHS .…”

mentioning

confidence: 99%

Fluidity properties and liquid composition of erythrocyte membranes in Chediak-Higashi syndrome.

Ingraham

Burns

Boxer

et al. 1981

The Journal of Cell Biology

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We have earlier shown through electron spin resonance (ESR) studies of leukocytes that membranes of cells from both Chediak-Higashi syndrome (CHS) mice and humans have abnormally high fluidity . We have extended our studies to erythrocytes . Erythrocytes were labeled with the nitroxide-substituted analogue of stearic acid, 2-(3-carboxypropyl)-4,4-dimethyl-2-tridecyl-3-oxazolidinyloxyl, and ESR spectra were obtained . Order parameter, S, at 23°C, was 0.661 and 0.653 for erythrocytes of normal and CHS mice (P < 0.001) . S was 0.684 for normal human erythrocytes and 0.675 (P < 0.001) for CHS erythrocytes at 25°C. Because S varies inversely to fluidity, these results indicate that CHS erythrocytes tend to have higher fluidity than normal . In vitro treatment of both mice and human CHS erythrocytes with 10 mM ascorbate returned their membrane fluidity to normal . We prepared erythrocyte ghosts and extracted them with CHC1 3:CH3OH (2 :1) . Gas-liquid chromatography analysis showed a greater number of unsaturated fatty acids for CHS . The average number of double bonds detected in fatty acids for mice on a standard diet was 1 .77 for normal and 2.02 for CHS (P < 0.04) ; comparison of human erythrocytes from one normal control and one CHS patient showed a similar trend . Our results suggest that an increased proportion of unsaturated fatty acids may contribute to increased fluidity of CHS erythrocytes . Our observation that both leukocytes and erythrocytes of CHS have abnormal fluidity indicates that CHS pathophysiology may relate to a general membrane disorder.

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Alteration of Sphingolipid Metabolism in Leukocytes from Patients with the Chediak–Higashi Syndrome

Cited by 24 publications

References 18 publications

Membrane Fluidity in Human and Mouse Chediak-Higashi Leukocytes

Membrane Fluidity in Human and Mouse Chediak-Higashi Leukocytes

Abnormal down-regulation of PKC is responsible for giant granule formation in fibroblasts from CHS (beige) mice—a thiol proteinase inhibitor, E-64-d, prevents giant granule formation in beige fibroblasts

Fluidity properties and liquid composition of erythrocyte membranes in Chediak-Higashi syndrome.

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