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Inhibition of cytolytic T lymphocyte activity by oxysterols

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Lipids

Abstract

The objective of this study was to investigate the effects of oxysterols (OS), namely 5α-hydroxy-6-ketocholestanol, 6-ketocholestanol and 25-hydroxycholesterol, on specific cell-mediated cytotoxicity by C57BL/6 spleen cells against P815-X2 (a DBA/2 mastocytoma) target cells. Cytolytic T lymphocytes (CTL) were generated by intraperitoneally injecting C57BL/6 mice with P815-X2 tumor cells 10 d prior to the cytotoxicity experiments. Preincubation of CTL with 10−5 M 5α-hydroxy-6-ketocholestanol and 6-ketocholestanol for 45 min in lipoprotein-depleted medium resulted in an inhibition of cytolytic activity (73 and 43%, respectively) as measured by 4-h51Cr release. At a concentration of 5×10−6 M, 5α-hydroxy-6-ketocholestanol inhibited CTL activity by 65%, whereas 6-ketocholestanol did not elicit any inhibition. By contrast, 25-hydroxycholesterol did not inhibit CTL at either concentration, although it is known to be a potent inhibitor of 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase, the rate-limiting enzyme in the cholesterol biosynthetic pathway. When CTL were preincubated with OS in lipoprotein-replete medium, there was no inhibition of CTL activity at the respective concentrations. The results suggest that the inhibition of CTL activity upon short-term incubation with OS is not due to the inhibition of cholesterol synthesis, but may be due to the insertion of OS into the plasma membrane to replace cholesterol and alteration of membrane physical properties.

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Abbreviations

ABS:

human blood group AB serum

CTL:

cytolytic T lymphocyte

H-2:

mouse major histocompatibility complex

HMG-CoA:

3-hydroxy-3-methylglutaryl coenzyme A

LPDM:

lipoprotein-depleted medium

LPDS:

lipoprotein-depleted serum

NK:

natural killer

OS:

oxysterol

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Authors and Affiliations

  1. Section of Hematology/Oncology, Chicago Medical School, 60064, North Chicago, Illinois

    Ömer Küçük, Jeanette Stoner-Picking, Leonard J. Lis & Maxwell P. Westerman

  2. Veterans Affairs Medical Center, 60064, North Chicago, Illinois

    Ömer Küçük & Jeanette Stoner-Picking

  3. Section of Hematology/Oncology, University of Chicago, 60637, Chicago, Illinois

    Stanley Yachnin

  4. Section of Hematology/Oncology, Northwestern, University Medical School, 60611, Chicago, Illinois

    Leo I. Gordon & R. Michael Williams

Authors
  1. Ömer Küçük
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  2. Jeanette Stoner-Picking
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  3. Stanley Yachnin
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  4. Leo I. Gordon
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  5. R. Michael Williams
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  6. Leonard J. Lis
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  7. Maxwell P. Westerman
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Küçük, Ö., Stoner-Picking, J., Yachnin, S. et al. Inhibition of cytolytic T lymphocyte activity by oxysterols. Lipids 29, 657–660 (1994). https://doi.org/10.1007/BF02536101

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  • DOI: https://doi.org/10.1007/BF02536101

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