Modulation of human lymphocyte responses by low density lipoproteins (LDL)

Enhancement but not immunosuppression is mediated by LDL receptors

J. A. Cuthbert, P. E. Lipsky

Research output: Contribution to journalArticle

26 Citations (Scopus)

Abstract

The role of low density lipoprotein (LDL) receptors in mediating the immunodulatory effects of LDL was examined by comparing responses of normal lymphocytes with those obtained from a patient with familial hypercholesterolemia (FH) lacking receptors for LDL. The function of LDL receptors in supporting lymphocyte growth was demonstrated by blocking endogenous sterol synthesis with mevinolin, a specific inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A reductase, and culturing cells in lipoprotein-deficient medium with supplemental LDL as the only source of cholesterol. Mevinolin inhibited mitogen-induced proliferation of normal and FH lymphocytes. Whereas inhibition was overcome by mevalonate, the product of the inhibited enzyme, low concentrations of LDL (< 10 μg of protein/ml) restored the responses of normal but not FH lymphocytes. When normal and FH lymphocytes were cultured in the absence of mevinolin, high concentrations of LDL (> 100 μg of protein/ml) inhibited mitogen-induced lymphocyte proliferation. The inhibitory effects on normal and FH lymphocytes were similar in that both required comparably large concentrations of LDL and could be completely reversed by transferrin. When normal lymphocytes were cultured in serum-free medium supplemented with transferrin, low concentrations of LDL (< 10 μg of protein/ml) caused marked augmentation of proliferation. By contrast, no enhancement of FH lymphocyte growth was observed. These results indicate that LDL-mediated enhancement of lymphocyte growth in the presence or absence of endogenous sterol biosynthesis involves specific receptors for LDL whereas the immunosuppression caused by LDL is independent of these receptors. Moreover, the results suggest that peripheral lymphocytes can be used to evaluate the functional integrity of the receptor-mediated uptake of LDL.

Original languageEnglish (US)
Pages (from-to)4539-4543
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Volume81
Issue number14 I
StatePublished - 1984

Fingerprint

LDL Receptors
LDL Lipoproteins
Immunosuppression
Lymphocytes
Hyperlipoproteinemia Type II
Lovastatin
Sterols
Transferrin
Mitogens
Growth
Mevalonic Acid
Serum-Free Culture Media
Lipoproteins
Oxidoreductases
Proteins
Cholesterol
Enzymes

ASJC Scopus subject areas

  • General
  • Genetics

Cite this

@article{c16aa9755d5d47de8b93df0105628ccd,
title = "Modulation of human lymphocyte responses by low density lipoproteins (LDL): Enhancement but not immunosuppression is mediated by LDL receptors",
abstract = "The role of low density lipoprotein (LDL) receptors in mediating the immunodulatory effects of LDL was examined by comparing responses of normal lymphocytes with those obtained from a patient with familial hypercholesterolemia (FH) lacking receptors for LDL. The function of LDL receptors in supporting lymphocyte growth was demonstrated by blocking endogenous sterol synthesis with mevinolin, a specific inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A reductase, and culturing cells in lipoprotein-deficient medium with supplemental LDL as the only source of cholesterol. Mevinolin inhibited mitogen-induced proliferation of normal and FH lymphocytes. Whereas inhibition was overcome by mevalonate, the product of the inhibited enzyme, low concentrations of LDL (< 10 μg of protein/ml) restored the responses of normal but not FH lymphocytes. When normal and FH lymphocytes were cultured in the absence of mevinolin, high concentrations of LDL (> 100 μg of protein/ml) inhibited mitogen-induced lymphocyte proliferation. The inhibitory effects on normal and FH lymphocytes were similar in that both required comparably large concentrations of LDL and could be completely reversed by transferrin. When normal lymphocytes were cultured in serum-free medium supplemented with transferrin, low concentrations of LDL (< 10 μg of protein/ml) caused marked augmentation of proliferation. By contrast, no enhancement of FH lymphocyte growth was observed. These results indicate that LDL-mediated enhancement of lymphocyte growth in the presence or absence of endogenous sterol biosynthesis involves specific receptors for LDL whereas the immunosuppression caused by LDL is independent of these receptors. Moreover, the results suggest that peripheral lymphocytes can be used to evaluate the functional integrity of the receptor-mediated uptake of LDL.",
author = "Cuthbert, {J. A.} and Lipsky, {P. E.}",
year = "1984",
language = "English (US)",
volume = "81",
pages = "4539--4543",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
number = "14 I",

}

TY - JOUR

T1 - Modulation of human lymphocyte responses by low density lipoproteins (LDL)

T2 - Enhancement but not immunosuppression is mediated by LDL receptors

AU - Cuthbert, J. A.

AU - Lipsky, P. E.

PY - 1984

Y1 - 1984

N2 - The role of low density lipoprotein (LDL) receptors in mediating the immunodulatory effects of LDL was examined by comparing responses of normal lymphocytes with those obtained from a patient with familial hypercholesterolemia (FH) lacking receptors for LDL. The function of LDL receptors in supporting lymphocyte growth was demonstrated by blocking endogenous sterol synthesis with mevinolin, a specific inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A reductase, and culturing cells in lipoprotein-deficient medium with supplemental LDL as the only source of cholesterol. Mevinolin inhibited mitogen-induced proliferation of normal and FH lymphocytes. Whereas inhibition was overcome by mevalonate, the product of the inhibited enzyme, low concentrations of LDL (< 10 μg of protein/ml) restored the responses of normal but not FH lymphocytes. When normal and FH lymphocytes were cultured in the absence of mevinolin, high concentrations of LDL (> 100 μg of protein/ml) inhibited mitogen-induced lymphocyte proliferation. The inhibitory effects on normal and FH lymphocytes were similar in that both required comparably large concentrations of LDL and could be completely reversed by transferrin. When normal lymphocytes were cultured in serum-free medium supplemented with transferrin, low concentrations of LDL (< 10 μg of protein/ml) caused marked augmentation of proliferation. By contrast, no enhancement of FH lymphocyte growth was observed. These results indicate that LDL-mediated enhancement of lymphocyte growth in the presence or absence of endogenous sterol biosynthesis involves specific receptors for LDL whereas the immunosuppression caused by LDL is independent of these receptors. Moreover, the results suggest that peripheral lymphocytes can be used to evaluate the functional integrity of the receptor-mediated uptake of LDL.

AB - The role of low density lipoprotein (LDL) receptors in mediating the immunodulatory effects of LDL was examined by comparing responses of normal lymphocytes with those obtained from a patient with familial hypercholesterolemia (FH) lacking receptors for LDL. The function of LDL receptors in supporting lymphocyte growth was demonstrated by blocking endogenous sterol synthesis with mevinolin, a specific inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A reductase, and culturing cells in lipoprotein-deficient medium with supplemental LDL as the only source of cholesterol. Mevinolin inhibited mitogen-induced proliferation of normal and FH lymphocytes. Whereas inhibition was overcome by mevalonate, the product of the inhibited enzyme, low concentrations of LDL (< 10 μg of protein/ml) restored the responses of normal but not FH lymphocytes. When normal and FH lymphocytes were cultured in the absence of mevinolin, high concentrations of LDL (> 100 μg of protein/ml) inhibited mitogen-induced lymphocyte proliferation. The inhibitory effects on normal and FH lymphocytes were similar in that both required comparably large concentrations of LDL and could be completely reversed by transferrin. When normal lymphocytes were cultured in serum-free medium supplemented with transferrin, low concentrations of LDL (< 10 μg of protein/ml) caused marked augmentation of proliferation. By contrast, no enhancement of FH lymphocyte growth was observed. These results indicate that LDL-mediated enhancement of lymphocyte growth in the presence or absence of endogenous sterol biosynthesis involves specific receptors for LDL whereas the immunosuppression caused by LDL is independent of these receptors. Moreover, the results suggest that peripheral lymphocytes can be used to evaluate the functional integrity of the receptor-mediated uptake of LDL.

UR - http://www.scopus.com/inward/record.url?scp=0021135912&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0021135912&partnerID=8YFLogxK

M3 - Article

VL - 81

SP - 4539

EP - 4543

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 14 I

ER -