Glutamine Protects Activated Human T Cells from Apoptosis by Up-Regulating Glutathione and Bcl-2 Levels

doi:10.1006/clim.2002.5257

Clinical Immunology

Volume 104, Issue 2, August 2002, Pages 151-160

https://doi.org/10.1006/clim.2002.5257 Get rights and content

Abstract

Glutamine is the most abundant amino acid in the body. A decrease of plasma glutamine concentrations is found in catabolic stress and is related to susceptibility to infections. Glutamine is known to modulate lymphocyte activation; however, little is known about glutamine modulation of cell death of activated human T cells. Using Jurkat T cells, we investigated glutamine modulation of T-cell apoptosis activated by PMA plus ionomycin. We found that glutamine at various concentrations significantly enhanced IL-2 production, cell proliferation, and cell viability of Jurkat T cells. Glutamine also decreased the number of apoptotic cells stimulated with PMA plus ionomycin as demonstrated by flow cytometry. Meanwhile, glutamine down-regulated CD95 and CD95L expression, but up-regulated CD45RO and Bcl-2 expression in activated T cells. Further investigation of CD95-mediated caspase activities revealed that supplementation of glutamine significantly decreased caspase-3 and caspase-8 activities in activated T cells. Since oxidative stress is closely associated with induction of lymphocyte apoptosis, we found that glutamine significantly increased glutathione (GSH), but decreased reactive oxygen species levels in activated T cells. Blockade of intracellular GSH formation enhanced, but exogenous GSH supplementation decreased, activated T-cell apoptosis. Studying normal peripheral lymphoproliferation, we also found that the presence of glutamine increased lymphoproliferation as well as Bcl-2 and CD95 expression; but decreased CD95L and activation-induced T-cell death. Taken together, glutamine appeared to augment lymphoproliferation but suppressed activation-induced T-cell death in both Jurkat T cells and human peripheral T lymphocytes.

References (49)

A.N. Akbar et al.
Cellular environments and apoptosis: Tissue microenvironments control activated T-cell death
Immunol. Today
(1997)
J.P. Revillard et al.
Apoptosis: Potential for disease therapies
Immunol. Today
(1998)
T.M. Buttke et al.
Oxidative stress as a mediator of apoptosis
Immunol. Today
(1994)
K. Banki et al.
Molecular ordering in HIV-induced apoptosis
J. Biol. Chem.
(1998)
M.K. Bauer et al.
Role of reactive oxygen intermediates in activation-induced CD95 ligand expression
J. Biol. Chem.
(1998)
M. Parry-Billings et al.
Does glutamine contribute to immunosuppression after major burn?
Lancet
(1990)
W.K. Chang et al.
Effect of glutamine on Th1 and Th2 cytokine responses of human peripheral blood mononuclear cells
Clin. Immunol.
(1999)
M.A. Pahlavani et al.
The effect of age on the expression of interleukin-2
Mech. Ageing Dev.
(1996)
K.D. Yang et al.
Hydroxyl radicals as an early signal involved in phorbol ester-induced monocytes differentiation of HL60 cells
Biochem. Biophys. Res. Commun.
(1994)
R.S. Douglas et al.
A simplified method for coordinate examination of apoptosis and surface phenotype of murine lymphocytes
J. Immunol. Methods
(1995)

C. Scaffidi et al.

Apoptosis signaling in lymphocytes

Curr. Opin. Immunol.

(1999)

V. Goossens et al.

The oxidative metabolism of glutamine: A modulator of reactive oxygen intermediate-mediated cytotoxicity of tumor necrosis factor in L929 fibrosarcoma cells

J. Biol. Chem.

(1996)

P.C. Calder

Glutamine and the immune system

Clin. Nutr.

(1994)

K. Brand et al.

Metabolism of glutamine lymphocytes

Metabolism

(1989)

C. Richter et al.

Oxidants in mitochondria: From physiology to disease

Biochem. Biophys. Acta

(1995)

L.V. Parijis et al.

Homeostasis and self-tolerance in the immune system: Turning lymphocytes off

Science

(1998)

L. Geneestier et al.

Apoptosis of activated peripheral T cells

Transplant. Proc.

(1999)

L.V. Parijis et al.

Role of Fas-mediated cell death in the regulation of immune responses

Curr. Opin. Immunol.

(1996)

T. Chiba et al.

Fas-mediated apoptosis is modulated by intracellular glutathione in human T cells

Eur. J. Immunol.

(1996)

N. Sato et al.

Thiol-mediated redox regulation of apoptosis: Possible roles of cellular thiols other than glutathione in T cell apoptosis

J. Immunol.

(1995)

D.C. Gore et al.

Glutamine kinetics in burn patients comparison with hormonally induced stress in volunteers

Arch. Surg.

(1994)

E.A. Newsholme

The possible role of glutamine in some cells of the immune system and the possible consequence for the whole animal

Experientia

(1996)

E. Roth et al.

Glutamine: An anabolic effect?

J. Parenter. Enter. Nutr.

(1990)

T. Rohde et al.

Glutamine, lymphocyte proliferation and cytokine production

Scand. J. Immunol.

(1996)

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¹: To whom correspondence should be addressed at Department of Medical Research, Kuang Tien General Hospital, Hung Kuang Institute of Technology, 34 Chung-Chie Rd, Sha-Lu, Taichung 433, Taiwan. Fax: 886-4-26310744. E-mail: [email protected].

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Regular ArticleGlutamine Protects Activated Human T Cells from Apoptosis by Up-Regulating Glutathione and Bcl-2 Levels

Abstract

Immunol. Today

Immunol. Today

Immunol. Today

J. Biol. Chem.

J. Biol. Chem.

Lancet

Clin. Immunol.

Mech. Ageing Dev.

Biochem. Biophys. Res. Commun.

J. Immunol. Methods

Curr. Opin. Immunol.

J. Biol. Chem.

Clin. Nutr.

Metabolism

Biochem. Biophys. Acta

Homeostasis and self-tolerance in the immune system: Turning lymphocytes off

Science

Apoptosis of activated peripheral T cells

Transplant. Proc.

Role of Fas-mediated cell death in the regulation of immune responses

Curr. Opin. Immunol.

Fas-mediated apoptosis is modulated by intracellular glutathione in human T cells

Eur. J. Immunol.

Thiol-mediated redox regulation of apoptosis: Possible roles of cellular thiols other than glutathione in T cell apoptosis

J. Immunol.

Glutamine kinetics in burn patients comparison with hormonally induced stress in volunteers

Arch. Surg.

The possible role of glutamine in some cells of the immune system and the possible consequence for the whole animal

Experientia

Glutamine: An anabolic effect?

J. Parenter. Enter. Nutr.

Glutamine, lymphocyte proliferation and cytokine production

Scand. J. Immunol.

Regular Article
Glutamine Protects Activated Human T Cells from Apoptosis by Up-Regulating Glutathione and Bcl-2 Levels