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Institute of Immunology and Transfusion Medicine, University of Lübeck School of Medicine, Lübeck, Germany
2To whom correspondence should be addressed.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONZinc deficiencyZinc therapyZinc in innate immunityZinc and T cellsDirect effects of zinc...Molecular basis of zinc-mediated...Zinc-altered activity of...REFERENCES |
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by leukocytes in the
healthy elderly person is correlated with low zinc serum level. The
defect in interferon- production is reconstituted by the addition of
physiologic amounts of zinc in vitro. Interestingly, zinc induces
cytokine production by isolated leukocytes. Zinc induces monocytes to
produce interleukin-1, interleukin-6 and tumor necrosis factor- in
peripheral blood mononuclear cells and separated monocytes. This effect
is higher in serum-free medium. However, only in the presence of
serum does zinc also induce T cells to produce lymphokines. This effect
on T cells is mediated by cytokines produced by monocytes. Stimulation
also requires cell-to-cell contact of monocytes and T cells.
Information is presented to illustrate the concepts that the zinc
concentration must be taken into account whenever in vitro studies are
made or complex alterations of immune functions are observed in
vivo.
KEY WORDS: • trace elements • immunology • cell biology • human • review
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONZinc deficiencyZinc therapyZinc in innate immunityZinc and T cellsDirect effects of zinc...Molecular basis of zinc-mediated...Zinc-altered activity of...REFERENCES |
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,
Vallee and Falchuk 1993
). The immune system is strongly
influenced by zinc, because it is one of the most highly proliferative
organs. Furthermore, zinc specifically interacts with components of the
immune system. The important role of zinc as an essential trace element
for immune function has already been well established (Bach 1981
, Crea et al. 1990
,
Cunningham-Rundles et al. 1980
, Good 1981
, Keen and Gershwin 1990
,
Kruse-Jarres 1989
, Wellinghausen et al. 1997
, Wellinghausen and Rink 1998
). However,
progress in determining the molecular principles of action of this ion
was made recently. In this review, advances in the field of zinc
immunology are focused on the interaction of zinc with human leukocytes
on a cellular and molecular basis, the influence on immunostimulants
and the therapeutic use of zinc. This review critically reflects the
importance of knowledge about the zinc status for the interpretation of
in vivo observations and in vitro experiments with leukocytes. |
Zinc deficiency |
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TOPABSTRACTINTRODUCTIONZinc deficiencyZinc therapyZinc in innate immunityZinc and T cellsDirect effects of zinc...Molecular basis of zinc-mediated...Zinc-altered activity of...REFERENCES |
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). However, it represents a very mobile and immunologically
important pool. Zinc is transported to cells bound to proteins,
predominantly albumin, 2-macroglobulin
and transferrin, but only free zinc ions seem to be biologically active
(Borth and Luger 1989
, Gless et al. 1992
,
Phillips 1976
, Vallee and Falchuk 1993
).
The function of 2-macroglobulin is regulated
by zinc itself. Zinc alters the structure of
2-macroglobulin and enhances its interaction
with cytokines and proteases, and in this way, it indirectly influences
immune function (Borth and Luger 1989
, James 1990
).
Various diseases associated with an impaired immune response are
characterized by low plasma zinc levels or a noticeable zinc
deficiency. Zinc absorption and nutritional aspects of zinc status are
beyond the scope of this article and are reviewed in detail by others
(Prasad 1995
, Vallee and Falchuk 1993
).
Zinc deficiency can be studied in the zinc-specific malabsorption
syndrome, acrodermatitis enteropathica, a rare autosomal recessive
inheritable disease (Neldner and Hambidge 1975
). This
extreme form of zinc deficiency shows thymic atrophy and a high
frequency of bacterial, viral and fungal infections. Untreated, this
disease is lethal within a few years, but pharmacologic zinc
supplementation can reverse all symptoms (Neldner and Hambidge 1975
). Impairment of immune function has been attributed to
zinc deficiency in other conditions like malnutrition and in certain
malignancies as well (Good 1981
, Prasad et al. 1997
, Schloen et al. 1979
). Furthermore, a
decreased serum zinc level is observed in chronic inflammatory or
infectious diseases. This often reflects a redistribution of serum zinc
into the liver within the acute phase reaction, caused by increased
production of proinflammatory cytokines, mainly interleukin
(IL)3
-1and IL-6, and the subsequent induction of zinc-binding
metallothionein in hepatocytes (Kushner 1982
,
Singh et al. 1991
).
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Zinc therapy |
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TOPABSTRACTINTRODUCTIONZinc deficiencyZinc therapyZinc in innate immunityZinc and T cellsDirect effects of zinc...Molecular basis of zinc-mediated...Zinc-altered activity of...REFERENCES |
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, Neldner and Hambidge 1975
). A major and
unresolved question is the optimal therapeutic dosage of zinc. The
dosage to reverse zinc deficiency should be adapted to the actual
requirements to avoid negative effects on the immune system. Therefore,
the control of plasma zinc concentration, not exceeding 30 µmol/L,
may be a limiting factor, as discussed later. However, the
immunosuppressive effect of zinc may be a completely new therapeutic
tool for the selective suppression of lymphocyte functions. In
comparison to conventional immunosuppressive drugs, zinc has the
advantage of being extremely nontoxic, even in dosages well exceeding
the recommended dietary intake (Fosmire 1990
).
Interestingly, in rheumatoid arthritis, an autoreactive T-cell
disease, diminished plasma zinc levels have been reported (Naveh et al. 1997
). Oral application of zinc sulfate over a 12-wk
period has shown a clear clinical benefit with regard to joint
swelling, morning stiffness and estimation of overall disease activity
in rheumatoid arthritis patients (Simkin 1976
). This
effect might be due to the T-cell inhibitory influence of zinc.
Low serum zinc levels and impaired immunologic functions are reported
in patients undergoing hemodialysis and in elderly individuals,
selected according to the immunogerontologic SENIEUR (Lighart et al. 1984
) protocol (Bonomini et al. 1993
,
Cakman et al. 1996
, Fraker et al. 1986
,
Sandstaed et al. 1982
). Significantly, decreased zinc
values (Bonomini et al. 1993
) or concentrations at the
lower limits of the normal range (perhaps due to zinc supplementation
via the dialysate) are described in hemodialysis patients. These low
zinc level have clinical relevance because they are related to an
impaired immune response to diphtheria vaccination (Kreft et al. 2000
).
The immune defects in elderly individuals mainly concern
cell-mediated immunity, including a diminished T-cell count,
dysfunction of T helper cell subpopulations and a decreased secretion
of interferon (IFN)- after virus stimulation in vitro (Cakman et al. 1996
, Sandstaed et al. 1982
).
Interestingly, the plasma zinc levels are significantly lower compared
with the control groups but still within the normal range
(Cakman et al. 1996
), a situation similar to that seen
in hemodialysis patients. The diminished IFN- secretion by elderly
individuals has been fully reconstituted by the in vitro addition of
zinc. However, high dose zinc supplementation, achieving 7–8 times the
physiologic value, blocks IFN- induction in elderly individuals
(Cakman et al. 1997
). Zinc has also been shown to be
effective in the treatment of the common cold (Al-Nakib et al. 1987
, Eby et al. 1984
, Mossad et al. 1996
), but there are several possible explanations for this
effect (Bashford et al. 1986
, Korant and Butterworth 1976
, Pasternak 1986
, Ratka et al. 1989
), which are discussed in detail by P.
Fraker and J. L. Jackson in this supplement. There are limited data
about zinc status in human immunodeficiency virus–infected patients. A
decreased serum zinc level is repeatedly reported for human
immunodeficiency virus–infected patients, but the relationship between
zinc status and disease progression is conflicting (Baum et al. 1995
, Beach et al. 1992
, Koch et al. 1996
). Independent of disease progression, hypozincemia has
been associated with a higher incidence of opportunistic bacterial
infections (Koch et al. 1996
), and oral zinc
supplementation leads to an increase in the CD4 count and to a reduced
incidence of opportunistic infections (Isa et al. 1992
,
Mocchegiani et al. 1995b
). These reports clearly show
that zinc supplementation has some clinical benefit by restoring
impaired immune function. However, the molecular basis of these effects
is largely unknown (Rice et al. 1995
). Furthermore, zinc
influences the in vitro systems to investigate the immune response.
Some of the molecular mechanisms of zinc treatment and the interference
with immunostimulants are discussed next.
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Zinc in innate immunity |
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TOPABSTRACTINTRODUCTIONZinc deficiencyZinc therapyZinc in innate immunityZinc and T cellsDirect effects of zinc...Molecular basis of zinc-mediated...Zinc-altered activity of...REFERENCES |
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, Keen and Gershwin 1990
). The p58 killer cell inhibitory receptor (KIR) on NK
cells requires zinc for the recognition of major histocompatibility
complex (MHC) class I molecules on target T cells (Rajagopalan et al. 1995
). Zinc may not only influence NK cell–mediated
killing but also could modulate cytolytic T-cell activity
(Mingari et al. 1998
). Besides reduced NK- and
T-cell functions, a reduced capability of mononuclear phagocytes to
kill intracellular Trypanosoma cruzi has been reported in
zinc-deficiency states (Cook-Mills et al. 1990
,
Wirth et al. 1989
). The deprivation of essential
nutrients such as iron and zinc represents a simple but effective
mechanism to fight foreign pathogens. The S-100
Ca2+ binding protein calprotectin (formerly known
as L1 protein) chelates zinc when released by the degradation of
neutrophils. Zinc chelation within abscesses inhibits the reproduction
of bacteria and Candida albicans (Clohessy and Golden 1995
, Murthy et al. 1993
, Sohnle et al. 1991
). |
Zinc and T cells |
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TOPABSTRACTINTRODUCTIONZinc deficiencyZinc therapyZinc in innate immunityZinc and T cellsDirect effects of zinc...Molecular basis of zinc-mediated...Zinc-altered activity of...REFERENCES |
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), confirming that zinc interferes with the earliest steps
of T-cell maturation. This effect depends in part on the regulation
of thymulin, an important thymic hormone secreted by thymic epithelial
cells (Dardenne et al. 1982
, Hadden 1992
). For thymulin, zinc is an essential cofactor.
Differentiation of immature T cells in the thymus is induced by
thymulin. Furthermore, thymulin regulates the functions of mature T
cells in the periphery. Modulation of cytokine secretion by peripheral
blood mononuclear cells (PBMC) and proliferative effects on CD8 T cells
in combination with IL-2 were reported for thymulin (Coto et al. 1992
, Safie-Garabedian et al. 1993
). The
expression of the high affinity receptor for IL-2 on mature T cells
(Tanaka et al. 1989
) is induced by thymulin. This is in
agreement with the observation that zinc deficiency is associated with
decreased T-cell proliferation after mitogen stimulation
(Crea et al. 1990
, Dowd et al. 1986
).
Zinc regulates lymphocyte homeostasis not only by maintaining
proliferation but also by suppressing death, namely through the
inhibition of apoptosis as discussed by Peter Zalewski in the present
supplement (Sundermann 1995
, Zalewski and Forbes 1993
). However, cell activation by zinc could also prevent the
cells from undergoing apoptosis. |
Direct effects of zinc on mononuclear cells |
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TOPABSTRACTINTRODUCTIONZinc deficiencyZinc therapyZinc in innate immunityZinc and T cellsDirect effects of zinc...Molecular basis of zinc-mediated...Zinc-altered activity of...REFERENCES |
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, Kirchner and Rühl 1970
, Rühl et al. 1971
).
More recently, it was discovered that zinc induces a specific cytokine
response in human PBMC. Zinc stimulated PBMC in a dose-dependent
manner to release IL-1, IL-6, tumor necrosis factor (TNF)- and
IFN-
((Driessen et al. 1994
, Salas and Kirchner 1987
, Scuderi 1990
). IL-1, IL-6 and
TNF- are directly induced in monocytes by zinc. This effect is
independent of the presence of lymphocytes, because separated monocytes
and monocytic cell lines respond to zinc (Driessen et al. 1994
). At least for TNF- it has been shown that cytokine
release after zinc stimulation is caused by the induction of mRNA
transcription rather than by the enhanced translation or stabilization
of already expressed mRNA (Wellinghausen et al. 1996a
).
In contrast to the direct stimulation of monocytes, the stimulative
effect on T cells represents an indirect effect that is dependent on
monocytes in the culture (Driessen et al. 1994
,
Rühl and Kirchner 1978
, Wellinghausen et al. 1997
). IFN- and sIL-2 receptor release by T
cells is mediated by monocyte-released IL-1 and IL-6 and a
cell-to-cell contact between monocytes and T cells (Driessen et al. 1994
, Wellinghausen et al. 1997
). Zinc fails
to induce cytokine production in isolated and monocyte-depleted T
cells (Hadden 1995
, Wellinghausen et al. 1997
), B cells (Crea et al. 1990
), NK cells
(Crea et al. 1990
) or neutrophils (Rink et al. unpublished results). Despite the different response of
these leukocyte subsets, the zinc-mediated activation of monocytes
and T cells is strongly regulated by the protein composition of the
culture medium. Insulin and transferrin, common supplements in
serum-free cell culture media, specifically enhance
zinc-induced monocyte activation by a non–receptor-dependent
mechanism (Crea et al. 1990
, Driessen et al. 1995c
, Phillips and Azari 1974
,
Wellinghausen et al. 1996b
). However, complete fetal
calf serum in the culture medium prevents monocyte stimulation by low
zinc concentrations due to binding of free zinc ions. In serum-free
culture medium, higher zinc concentration (~100 µM) stimulates
monocytes but inhibits T-cell functions. This may depend on the
cellular tolerance of zinc in these leukocyte subsets. T cells have a
lower intracellular zinc concentration than monocytes. Furthermore, T
cells are more susceptible to increasing zinc levels than monocytes
(Bulgarini et al. 1989
, Goode et al. 1989
). In conclusion, indirect T-cell stimulation by zinc
takes place only in concentrations high enough for monokine induction
but not exceeding the critical concentration for T-cell
suppression. The physiologic zinc level obviously represents a
concentration that ensures optimally balanced T-cell function.
We recently discovered a zinc-dependent mechanism of T-cell
inhibition. IL-1–dependent proliferation of the T cell line D10 is
inhibited by high zinc concentration. The molecular basis of this
effect is the zinc-specific inhibition of the IL-1 type I
receptor–associated kinase at a concentration that represents ~8
times the physiologic serum level (Wellinghausen et al. 1997
). This in vitro observation correlates with the T cells’
inhibitory effect after high dose zinc supplementation in vivo as
observed in clinical studies (Chandra 1984
,
Duchateau et al. 1981
). Interestingly, much lower
concentrations of zinc, representing 3–4 times the physiologic zinc
level, inhibit alloreactivity in the mixed lymphocyte culture model
(aCampo C., Wellinghausen, N., Faber, C., Fischer, A. & Rink, L.
unpublished results).
As described, high zinc concentrations are inhibitory for T-cell
functions, but sometimes T-cell functions also are dysregulated in
moderate zinc deficiency. For example, rheumatoid arthritis and other
diseases with autoreactive T-cell pathology are often associated
with low serum zinc levels (Simkin 1976
). Low zinc
intake during pregnancy and decreased plasma zinc levels correlate with
an increased risk of preterm delivery and abortion (Bedwal and Bahuguna 1994
, Favier 1992
, Jameson 1993
), which might reflect the activation of normally
suppressed alloreactive T cells. In conclusion, T-cell function is
delicately regulated by the concentration of zinc in the cell or
plasma.
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Molecular basis of zinc-mediated effects |
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TOPABSTRACTINTRODUCTIONZinc deficiencyZinc therapyZinc in innate immunityZinc and T cellsDirect effects of zinc...Molecular basis of zinc-mediated...Zinc-altered activity of...REFERENCES |
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, Mathe et al. 1985
, Phillips 1976
). However, data clearly
indicating CD71 as a zinc receptor are not available, and thus no
specific receptor that facilitates zinc uptake or triggers
intracellular messages has yet been confirmed. Zinc enters the cell
within minutes and its uptake increases a little during the first hours
(Naber et al. 1994
, Wellinghausen et al. 1996b
). Surprisingly, in contrast to its divergent effect on
monocytes and T cells, zinc uptake does not differ significantly in
either cell population (Wellinghausen et al. 1997
). The
majority of zinc that is taken up by PBMC is bound to proteins, because
the total intracellular zinc concentrations exceed the amount of free
zinc (Rink et al. unpublished results).
So far we have fragmentary information that zinc signaling does occur.
Protein tyrosine kinases, as well as cAMP- and cGMP-dependent
protein kinases, are clearly involved in zinc-mediated stimulation
(Wellinghausen et al. 1996b
). Furthermore, zinc
increases the activity of protein kinase C (PKC) and regulates its
intracellular translocation, but zinc is not part of the active center
(Csermely et al. 1988
, Zalewski et al. 1990
). Structural stabilization of PKC depends on a unique zinc
cluster motif (Vallee and Falchuk 1993
). However, an
involvement of PKC in zinc-induced signal transduction in PBMC has
not been confirmed (Wellinghausen et al. 1996b
). Zinc is
also integrated in the active center of phospholipase C, but its effect
on cell activation is questionable (Coleman 1992
).
Immunologically more important than a specific interaction of zinc with
certain molecules is a general influence of zinc on the fluidity of
lipids and thus also of biological membranes as discussed by others in
the present supplement (Bettger and O'Dell 1993
,
Chvapil 1976
, Kruse-Jarres 1989
).
|
Zinc-altered activity of immunostimulants |
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TOPABSTRACTINTRODUCTIONZinc deficiencyZinc therapyZinc in innate immunityZinc and T cellsDirect effects of zinc...Molecular basis of zinc-mediated...Zinc-altered activity of...REFERENCES |
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, Fraker et al. 1986
, Warner and Lawrence 1986
). Whether
this effect depends on an alteration of phytohemagglutinin or whether
zinc is really comitogenic is still unresolved. Another explanation is
that zinc enhances the activity of contaminating lipopolysaccharide
(LPS). Zinc, even in substimulatory concentrations, acts
synergistically with LPS with respect to cytokine induction in
leukocytes (Driessen et al. 1995a
and 1995b
). This
synergism is based on a specific zinc-induced structural alteration
of LPS. Through the addition of zinc, LPS is transformed in its
biologically more active, less-fluid form (Wellinghausen et al. 1996
). Due to the described synergism in even minimal,
substimulating concentrations of both LPS and zinc (Driessen et al. 1995c
), exceptional care must be exercised in cell culture
experiments to exclude unwanted effects.
In contrast to its synergism with LPS, zinc inhibits the function of
some bacterial superantigens (Driessen et al. 1995a
and 1995b
). Zinc inhibits only superantigens binding to the MHC
class-II ß-chain, like Staphylococcus aureus
enterotoxins (SE) A, D and E and the Mycoplasma
arthritidis superantigen (Bernatchez et al. 1997
,
Fraser et al. 1992
, Kim et al. 1994
,
Sundström et al. 1997). The interaction between
these superantigens and the MHC-II ß-chain is mediated by a zinc
cluster involving amino acids from the superantigen and histidine-81 of
the MHC-II ß-chain. High-dose zinc might saturate both sites
independently, thus preventing complex formation. The absence of a
zinc-binding motif in superantigens that bind only to the
MHC-II -chain explains the lack of inhibition by excess zinc.
Interestingly, zinc influences superantigens in a second way. SED
forms homodimers due to zinc bridges, which have the capacity for
T-cell–independent interaction with MHC-II molecules, resulting in
direct monocyte activation (Sundström et al. 1996
).
Zinc is important for leukocyte functions both in vivo and in vitro. The interaction within the immune system is complex and delicately regulated by zinc. Zinc deficiency leads to dysfunction of the immune system, but in addition, high doses of zinc have negative effects on leukocyte functions. Although knowledge about the molecular mechanisms of zinc has increased during the past years, we still do not know the most effective therapeutic dosage. From in vitro studies we learned that zinc levels of >30 µM were found to have more inhibiting than stimulating effects to the immune system. However, these inhibiting effects might be useful as a new therapeutic tool. Because most experimental systems in immunologic research depends on the stimulation of leukocytes in vivo or in vitro, the modulation of immunostimulants by zinc is a trap. Zinc-specific alteration of the activity of stimulants might mimic effects on the immune system. As a consequence, the zinc concentration should be considered whenever complex alterations of immune functions are observed in vivo or in vitro.
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FOOTNOTES |
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3 Abbreviations used: IFN, interferon; IL, interleukin; LPS, lipopolysaccharide; MHC, major histocompatibulity complex; NK, natural killer; PBMC, peripheral blood mononuclear cells; PKC, protein kinase C; TNF, tumor necrosis factor.
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REFERENCES |
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TOPABSTRACTINTRODUCTIONZinc deficiencyZinc therapyZinc in innate immunityZinc and T cellsDirect effects of zinc...Molecular basis of zinc-mediated...Zinc-altered activity of...REFERENCES |
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