REVIEW
Antioxidant and anti-inflammatory effects of zinc. Zinc-dependent
NF-jB signaling
Magdalena Jarosz
1
•
Magdalena Olbert
1
•
Gabriela Wyszogrodzka
2
•
Katarzyna Młyniec
3
•
Tadeusz Librowski
1
Received: 30 November 2016 / Accepted: 31 December 2016 / Published online: 12 January 2017
Ó The Author(s) 2017. This article is published with open access at Springerlink.com
Abstract Zinc is a nutritionally fundamental trace ele-
ment, essential to the structure and function of numerous
macromolecules, including enzymes regulating cellular
processes and cellular signaling pathways. The mineral
modulates immune response and exhibits antioxidant and
anti-inflammatory activity. Zinc retards oxidative processes
on a long-term basis by inducing the expression of metal-
lothioneins. These metal-binding cysteine-rich proteins are
responsible for maintaining zinc-related cell homeostasis
and act as potent electrophilic scavengers and cytoprot ec-
tive agents. Furthermore, zinc increases the activation of
antioxidant proteins and enzymes, such as glutathione and
catalase. On the other hand, zinc exerts its antioxidant
effect via two acute mechanisms, one of which is the sta-
bilization of protein sulfhydryls against oxidation. The
second mechanism consists in antagonizing transition
metal-catalyzed reactions. Zinc can exchange redox active
metals, such as copper and iron, in certain binding sites and
attenuate cellular site-specific oxidative injury. Studies
have demonstrated that physiological reconstitution of zinc
restrains immune activation, whereas zinc deficiency, in
the setting of severe infection, provokes a systemic
increase in NF-jB act ivation. In vitro studies have shown
that zinc decreases NF-jB activation and its target genes,
such as TNF-a and IL-1b, and increases the gene expres-
sion of A20 and PPAR-a, the two zinc finger proteins with
anti-inflammatory properties. Alternative NF-jB inhibitory
mechanism is initiated by the inhibition of cyclic nucleo-
tide phosphodiesterase, whereas another presumed
mechanism consists in inhibition of IjB kinase in response
to infection by zinc ions that have been imported into cells
by ZIP8.
Keywords Zinc Oxidative stress Inflammation
NF-jB signaling Protein A20 ZIP8
Zinc biology
In 1963, nearly a century after dem onstrating the essen-
tiality of zinc (Zn) for the growth of Aspergillus niger
(Raulin
1869), zinc deficiency in man was recognized and
described by Prasad et al. (
1963). Since then, the impact of
zinc on human health has been thoroughly investigated. To
date, numerous studies have shown that zinc, rather than
being a toxic transition metal, is a nutritionally funda-
mental non-toxic trace mineral (Fosmire 1990). It is neither
cytotoxic, nor carcinogenic, mutagenic or teratogenic
(Le
´
onard et al.
1986). In addition, the reported zinc
intoxications are rare and related primarily to copper
deficiency (Plum et al.
2010; Młyniec et al. 2015a; Merza
et al.
2015). On the other hand, deregulated homeostasis
and even marginal zinc deficiency pose significant risk to
healthy individuals.
Zinc, after iron, is second most prevalent trace element in
the human body (Vas
ˇ
a
´
k and Hasler
2000). The total amount
of zinc in adults is about 1.4–2.3 g, but its content varies
significantly between tissues. 85% of zinc is localized in the
muscles and bones, 11% in the skin and liver, and the
& Magdalena Jarosz
m.gawel.87@gmail.com
1
Department of Radioligands, Jagiellonian University Medical
College, Medyczna 9, 30-688 Krakow, Poland
2
Department of Pharmaceutical Technology and
Biopharmaceutics, Jagiellonian University Medical College,
Medyczna 9, 30-688 Krakow, Poland
3
Department of Pharmacobiology, Jagiellonian University
Medical College, Medyczna 9, 30-688 Krakow, Poland
Inflammopharmacol (2017) 25:11–24
DOI 10.1007/s10787-017-0309-4
Inflammopharmacology
123
remaining 4% in other tissues of the body (Calesnick and
Dinan
1988). Highest concentrations of zinc have been
determined in the retina and choroid of the eye, followed by
the prostate, bones, liver, and kidneys (Tipton et al.
1965;
Karcioglu
1982). Since zinc is present in each organ, tissue,
and fluid of the body, its deficiency proves crucial for human
well-being. Marginal-to-moderate deficiency leads to
growth retardation, poor appetite, impaired immunity,
enhanced oxidative stress, and increased generat ion of
inflammatory cytokines. Further symptoms include skin
reactions, delayed wound healing, and declined reproductive
capacity (Prasad et al.
1963, 2001, 2014b; Tapiero and Tew
2003; Lansdown et al. 2007). Adequate intake is of great
importance also to neuropsychological performance. Zinc
deficiency is increasingly associated with mental lethargy,
cognitive impairment, symptoms of depression, and Alz-
heimer&s disease (Adlard and Bush
2011; Szewczyk et al.
2011a, b; Gower-Winter and Levens on 2012; Maes et al.
2012; Młyniec et al. 2014, 2015b, 2015). Most severe clinical
manifestations of zinc deficiency are observed in acroder-
matitis enteropathica (AE). This rare inheritable autosomal
recessive metabolic disorder may become fatal if not rec-
ognized and treated instantly with zinc (Vallee and Falchuk
1993). To fully appreciate the significance of zinc to human
health, one needs to be aware of the great number of bio-
logical processes requiring zinc-containing proteins.
The element is essential to the structure and function of
about 2800 macromolecules and over 300 enzymes . It is a
component of about 10% of human proteins, including
transcription factor s and key enzymes regulating cellular
processes and cellular signaling path ways (Rink and Gab-
riel
2001; Andreini et al. 2006). Most of the zinc-
containing enzymes catalyze hydrolysis reactions, but
representatives of all enzyme classes are known (Vallee
and Falchuk
1993). The ion is critically responsible for cell
proliferation, differentiation, and apoptosis. The interme-
diary metabolism, DNA synt hesis, reproduction, vision,
taste, and cognition are all zinc-dependent. Studies have
shown that zinc safeguards DNA integrity and its defi-
ciency can impair the function of zinc-dependent proteins
involved in the DNA damage response (Yan et al.
2008).
Moreover, a growing body of evidence suggests that zinc
deficiency increases the concentrations of inflammatory
cytokines and oxidative stress, induces apoptosis, and
causes cell dysfunction. The element plays, therefore, a
preventive role against free radical formation and protects
biological structures from injury during inflammatory
processes (Powell
2000; Tapiero and Tew 2003; Stefanidou
et al.
2006; Chasapis et al. 2012).
Enumerating impressive structural, catalytic, and regu-
latory functions of zinc is beyond the scope of this article.
Nevertheless, the antioxidant and anti-inflammatory prop-
erties of zinc are discussed more particularly later.
Zinc homeostasis
The current RDAs (Recommended Dietary Allowances)
for zinc given by Institute of Medicine are 11 mg/day for
males and 8 mg/day for females (Institute of Medicine
(US) Panel on Micronutrients
2001). However, individual
requirements may vary widely depending on numerous
factors influencing zinc uptake and excretion, such as age,
stress, and illness conditions or applied diet (European
Commission, Health and Consumer protection directorate
general
2003). Zinc is the element with a minor plas ma
pool (13.8–22.9 lmol/L) and a rapid turnover (Bonaven-
tura et al.
2015). There is no store for zinc in the body and
the gastrointestinal tract is the main site for regulation of its
balance (Tapiero and Tew
2003). In healthy subjects, zinc
homeostasis can be efficiently maintained under conditions
of zinc excess or deprivation over a wide range of dietary
intake through modulation of its intestinal upta ke and
excretion (Jackson et al. 1984; Hambidge et al. 2010). Zinc
is absorbed primarily in the duodenum, ileum, and jejunum
by a carrier-mediated process or more rarely by passive
diffusion (Vallee and Falchuk
1993; Sian et al. 1993;
Tapiero and Tew
2003). After entering the duodenum
within 3 h zinc passes into the bloodstream. Distribution
occurs via the serum, where about 84% of zinc is bound to
albumin, 15% to a2-globulins, and 1% to amino acids
(Chesters and Will 1981; Foote and Delves 1984). In
multicellular organisms, virtually, all zinc is intracellular.
30–40% of zinc is localized in the nucleus, 50% in the
cytosol, organelles, and specialized vesicles, and the
remainder is associated with cell membranes (Vallee and
Falchuk
1993). The cellular homeostasis of zinc and its
intracellular distribution is controlled by specialized
transport and binding proteins. Zn
2?
transport through lipid
bilayers is mediated by two protein families; 14 ZIP (zinc
importer family, SLC 39A) and 10 ZNT (zinc transporter
family, SLC 30A) transporters (Lichte n and Cousins
2009).
ZNT proteins generally transport zinc ions out of the
cytosol, whe reas ZIP proteins import them from cellular
compartments or the extracellular space into the cytosol.
The two families of transporters precisely control zinc
availability due to tissue specific expression profiles and
different subcellular localizations.
Human homeostatic mechanisms maintain plasma zinc
within the reference range of approximately 10–18 lmol/L
(Foster and Samman
2012). However, an interpretation of
serum zinc levels may not be apparent. Plasma zinc rep-
resents only 0,1% of total body zinc and is an insensitive
marker for zinc deficiency. Immune cells may be the first to
respond to zinc deficiency even before plasma zinc.
Moreover, its biological variation is high and only a change
above 30% is likely to be significant. Finally,
12 M. Jarosz et al.
123
hypozincemia can be cause d by factors unrelated to zinc
status, such as ongoing acute phase response (APR) or
hypoalbuminemia (Livingstone
2015). Inflammatory pro-
cesses are associated with remar kable changes in zinc
homeostasis. The APR rapidly decreases the serum zinc
concentration due to the redistribution of zinc from plasma
into organs, predominantly the liver. The proinflammatory
cytokine IL-6 has been shown to up-regulate ZIP14 in
mouse liver (Liuzzi et al.
2005). Such decline in plasma
zinc has been suggested to be an adaptive response inten-
ded to deprive invading pathogens of zinc. At the same
time, macrophages increase the concentrations of zinc to
intoxicate phagocytosed microorganisms (Shankar and
Prasad
1998; Haase and Rink 2014). Moreover, hypoz-
incemia may be the consequence of chelation of zinc by the
zinc and calcium binding S-100 protein calprotectin, which
is released by leukocytes. Calprotectin has been shown to
suppress the reproduction of bacteria and Candida albicans
(Sohnle et al. 2000). On the other hand, increased intra-
cellular zinc serv es a role in energy metabolism, provides
efficient neutralization of reactive nitrogen and oxygen
species, and guarantees proper synthesis of proteins and
more specifically the synthesis of acute phase proteins in
the liver (Powanda et al.
1973; Haase and Rink 2009).
Therefore, zinc redistribution during inflammation may
serve multiple purposes.
Finally, zinc homeostasis maintenance is supported by
intracellular zinc binding proteins. Up to 20% of intracel-
lular zinc is complexed by metallothioneins (MTs). These
ubiquitous cysteine-rich proteins with a low-molecular
weight bind up to seven zinc ions, acting as a cellular zinc
buffer. They play a significant role in metal uptake, dis-
tribution, storage, and release (Cousins 1985 ; Vas
ˇ
a
´
k and
Hasler
2000). Maintaining physiological concentrations of
zinc and its tight control by MTs in each cell of the body is
necessary to avoid oxidative stress, since not only zinc
deficiency but also zinc overload are pro-oxidant condi-
tions (due to inhibition of mitochondrial respiration and
antioxidant enzymes) (Skulachev et al.
1967; Maret 2000).
In principle, the increase in the amount of zinc in applied
diet results in increase in MT concentration in enterocytes.
In addition, in turn, the higher MT levels, the less zinc is
further absorbed from gastrointestinal tract (Sullivan et al.
1998). By binding zinc and regulating zinc absorption, MT
protects the cell from its overload and releases the element
when necessary.
Zinc and metallothioneins
Metallothioneins are metal-binding proteins with high
affinity to divalent trace minerals, such as zinc and copper,
as well as to toxic cadmium and mercury ions. Their
presumed functions in the physiological condition include
heavy metal detoxification, metal storage, and donation to
target apometalloproteins (particularly to zinc finger pro-
teins and newly synthesized apoenzymes) (Cousins 1985;
Coyle et al.
2002; Kondoh et al. 2003). Serving as both
zinc acceptor and zinc donor and thereby controlling the
concentration of readily available zinc ions appears to be
the major and most important role of MT.
The cluster structure of the protein with two domains, in
each of which zinc ions are bound tetrahedrally to cys-
teines, precludes access of ligands to zinc. Zinc/sulphur
cluster with low redox potential is very sensitive to changes
of cellular redox state, and therefore, sulfhydryl groups of
MTs are readily oxidized by a number of mild cellular
oxidants with concomitant release of zinc. In brief, a shift
to more oxidizing conditions releases zinc, whereas a shift
to more reducing environment leads to its binding (Maret
1995; Maret and Vallee 1998). Zinc ions, only rapidly
released by MTs, are able to play its relevant function
against oxidative stress and participate in immune
responses. MTs are ipso facto the link between zinc and
cellular redox status of the cell (Krezel and Maret
2007).
Furthermore, as repeatedly confirmed in the previous
studies, MTs themselves act as potent electrophilic scav-
engers and cytoprotective agents against oxidative and
inflammatory injury (Andrews 2000; Kang et al. 2015).
They are able to capture a wide range of reactive oxygen
species (ROS), including superoxide, hydrogen peroxide,
hydroxyl radicals, and nitric oxide (Sato and Kondoh
2002;
Ruttkay-Nedecky et al.
2013). It has been shown that the
ability of MTs to scavenge hydroxyl radicals is 3009
higher than that of glutathione, the most abundant antiox-
idant in the cytosol (Sato
1992). Thus, under physiological
conditions, MTs can efficiently protect biological struc-
tures and DNA from the oxidative damage. Concerns may
be raised about the roles of MTs under pathophysiological
conditions.
Since proinflammatory cytokines, such as tumor necro-
sis factor TNF, IL-1, IL-6, and interferon-c, do induce
hepatic MT gene expression in vivo, the role of MT in
inflammatory processes needed to be examined (Waelput
et al.
2001; Inoue et al. 2009). Various types of inflam-
matory conditions have been studied (including allergic,
oxidative and LPS-related), in which MT has been shown
to protect against ovalbumin-induced allergic airway
inflammation, against ozone-induced lung inflammation,
and against coagulatory and fibrinolytic disturbances and
multiple organ damage induced by lipopolysaccharide
(LPS). Antioxidant effects of MT have also been confirmed
in response to exposure to radiation, ethanol, and toxic
anticancer drugs (Powell
2000). However, conflicting
results were also reported. Kimura et al. showed that
D-
galactosamine (GalN)-sensitized MT-null mice are more
Antioxidant and anti-inflammatory effects of zinc 13
123
sensitive to LPS-induced lethality presumably through the
reduction of protective a1-acid glycoprotein (AGP) than
wild-type mice, whereas Waelput et al. observed signifi-
cantly higher survival in MT-nu ll mice compared to wild-
type mice in TNF-induced lethal shock (Kimura et al.
2001; Waelput et al. 2001). Moreover, it was found that
TNF-a is likely to act as a final mediator of endotoxin
action in a sequence of events characterized by but not
limited to reactive oxygen species formation (Tiegs et al.
1989), which may partly explain the protection against
LPS/GalN but not against TNF/GalN by antioxidants. The
question then arises why MT-null animal s were more
resistant to TNF lethality in comparison with wild-type and
MT-overexpressing ones. The possible interpretation of
these findings is that increased MT expressio n contributes
to rapid redistribution of tissue zinc levels, which may
represent an acute disruption of zinc homeostasis (Wong
et al.
2007). Interestingly, Waelput et al. showed that zinc
depletion increased the sensitivity of both MT-null and
wild-type mice to TNF toxicity and that zinc sulphate-
pretreated animals were significantly protected against
TNF. The authors ascribe the zinc mediated protection
against TNF to metal responsive genes and more specifi-
cally to hsp70 gene, which is strongly induced in jejunum
after zinc sulphate treatment (Waelput et al.
2001).
Although the findings have significant implications for the
understanding of the substantial role of MT in stress con-
ditions, inflammation and infection, further studies will be
necessary to reveal the different roles of MT under
pathophysiological conditions.
Zinc in oxidative stress and inflammation
Oxidative stress underlies the molecular mechanisms
responsible for the development of many inflammatory
diseases, such as atherosclerosis, diabetes mellitus,
rheumatoid arthritis, cancer, and neurodegeneration (Valko
et al.
2007). It occurs when cellular antioxi dant systems
prove insufficient to remove increased ROS levels.
Although ROS play beneficial role in the immune response
to infection, their excess causes lipid peroxidation and
damage to proteins and nucleic acids (Castro and Freeman
2001).
Not only oxidative stress may lead to the inflammatory
response, but inflammation itself may provoke free radical
formation. A large amount of ROS and RNS is generated
by phagocytic cells, neutrophils, and macrophages, as part
of their essential role in host defense, in a mechanism
dependent from oxygen, also called the oxidative outburst.
The major intracellular sites of ROS production in
eukaryotic cells are mitochondrial electron transport chain,
peroxisomal long-chain fatty acid oxidation, and
respiratory burst mainly via activation of NADPH oxi-
dases. In addition, other enzymes , including cytochrome
P450 monooxygenase, nitric oxide synthase (NOS), xan-
thine oxidase, cyclooxygenase (COX), and lipoxygenase
(LOX), generate ROS through their enzymatic reaction
cycles (Bhattacharyya et al.
2014; Holmstro
¨
m and Finkel
2014). Furthermore, free radical chain reactions may be
induced by transition metals and in response to many
exogenous factor s, such as pollutants, ultraviolet radiation,
cigarette smoking, alcohol, and drugs, such as nonsteroidal
anti-inflammatory drugs (NSAIDs). Chronic infections and
inflammatory disorders also provoke the increas ed pro-
duction of free radicals (Bhattacharyya et al.
2014; Sharma
et al.
2014). Therefore, to comb at ROS, cells are equipped
with potent enzymatic and non-enzymatic antioxidant
defences.
Non-enzymatic antioxidants include glutathione (GSH),
thioredoxin (Trx), and melatonin. Antioxidant enzymatic
mechanisms involve enzymes, such as superoxide dismu-
tase (SOD), glutathione peroxidase (GPX), glutathione
reductase (GR), catalase (CAT), and heme oxygenase (HO)
(Castro and Freeman
2001; Rahman 2007; Bhattacharyya
et al.
2014). From all above mentioned, SOD and catalase
provide major antioxidant defences against ROS. Super-
oxide dismutase exists in several isoforms. Zinc is a co-
factor of cytosolic and extracellular Zn/Cu SOD enzyme,
which acts as an ROS scavenger by catalyzing the dis-
mutation of O
2
-
radical into the less harmful O
2
and H
2
O
2
(Mariani et al. 2008). Except against oxidative stress, the
efficacy of Zn/Cu SOD is also crucial for the resolution of
inflammation. Neutrophils recruited to the inflammation
sites generate ROS, protease enzymes, and chemokines.
Consequently, the healthy tissue is being damaged and
further influx of inflammatory cells is maintained. For the
reduction of inflammation, activated neutrophils must be
removed safely by apoptosis. As H
2
O
2
has been suggested
to be a possible major mediator of ROS-induced neutrophil
apoptosis in a caspase-dependent manner, the proper
functioning of SOD enzyme contributes to the regulation of
neutrophil apoptosis and neutrophil-mediated tissue injury
(Yasui et al.
2005, 2006). The more H
2
O
2
produced by Zn/
Cu SOD, and the more neutrophils undergo apoptosis.
Thus, zinc, as a component of SOD, procaspas e-3, and
other enzymes involved in neutrophil apoptosis, plays an
important role during inflammatory response (Zalewski
et al.
1993; Ho et al. 2004). Moreover, in a study by Goel
et al. (
2005), zinc treatment to chlorpyriphos-intoxicated
animals normalized the otherwise increased levels of lipid
peroxidation to within normal levels. Zinc treatment to
these animals elevated the levels of GSH, catalase, and
detoxifying glutathione-S-transferase (GST). Zinc has also
been proven to exhibit its antioxidant effect by inducing
14 M. Jarosz et al.
123
heme oxygenase and inhibiting NADPH oxidase (Tapiero
and Tew
2003; Prasad 2014b).
The critical transcription factor that regulates the
expression of genes encoding above mentioned antioxidant
and detoxifying molecules (GSH, SOD, GST, HO-1),
nuclear factor erythroid 2-related factor 2 (Nrf2), has been
proven to be up-regulated by zinc. Studies revealed sig-
nificantly increased oxidative damage and decreased Nrf2
expression in zinc-deficient mice (Zhao et al.
2010), as well
as increased HO-1 mRNA and Nfr2 protein levels in
human colon cancer HCT 116 cells in response to high
concentrations of zinc (Smith and Loo
2012). It has also
been shown that zinc can protect endothelial cells from
hydrogen peroxide via Nrf2-dependent stimulation of glu-
tathione biosynthesis (Cortese et al.
2008). Since zinc up-
regulates Nrf2, also through this pathway, it contributes to
the regulation of oxidative stress-induced cellular damage.
The antioxidant mechanisms, which involve zinc, can be
divided into acute and chronic. Chronic effects in response
to long-term exposure to zinc consist in induction of some
other ultimate antioxidant substances, above all, previously
described metallothioneins (MTs) (Cousins
1985; Powell
2000). Chronic zinc deficiency impairs the activity of MTs
and renders the organism more susceptible to injury
induced b y various oxidative stressors. On the other hand,
zinc retards oxidative processes via two acute mechanisms,
one of which is the stabilization of protein sulfhydryls
against oxidation (Bray and Bettger
1990; Powell 2000).
There are three ways proposed by Gibbs et al. (
1985), in
which zinc reduces sulfhydryl reactivity. First, zinc binds
directly to the thiol group. Second, it creates steric hin-
drance, by binding in the close proximity to the sulfhydryl
group of the protein. Third, it changes the conformation of
the protei n, by binding to the other site of the protein. The
most extensively studied enzyme for sulfhydryl protection
by zinc is d-aminolevulinate dehydratase, which catalyzes
the formation of the pyrrole porphobilinogen. The presence
of the metal prevents enzyme thiol oxidation and disul-
phide formation. Contrary, the removal of zinc increases
sulfhydryl reactivity resulting in the loss of dehydratase
activity (Powell
2000; Tapiero and Tew 2003). Other
examples of sulfhydryl-containing proteins protected by
zinc are DNA zinc-bindin g protei ns (zinc fingers), alanyl
tRNA synthetase, tubulin, and dihydroorotase (Moc-
chegiani et al.
2000; Rink and Gabriel 2001; Pace and
Weerapana
2014).
The second acute antioxidant effect of zinc consists in
antagonizing transition metal-catalyzed reactions, such as
reduction of OH formation from H
2
O
2
and O
2
-
(Powell
2000). Redox-active transition metals have been demon-
strated to catalyze formation of radicals, mainly through
Fenton reaction (Jomova and Valko
2011). Any OH
formed in this reaction attacks adja cent structures and
causes severe localized damage. The damage is all the
greater because in physiological media copper and iron
tend to associate with specific cellular components, such as
nucleotides and glucose for iron or DNA, carbohydrates,
enzymes, and proteins for copper. Transition metals bound
to molecules form the coord ination complex, which sub-
sequently, reacts with H
2
O
2
and forms OH radical. The
radical can then react with hydrogen attac hed to the car-
boxyl group of the molecule, thereby changing its
properties. These sites serve as loci for repetitive radical
formation through repeated redox cycling of the metals.
Transition metal-induced free radical chain reactions lead
to lipid peroxidation, DNA, and protein damage. Both iron
and copper play a critical role in initiation and propagation
of lipid peroxidation, which destructs lipid bilayers.
Overall, redox-active transition metals associated with
cellular components establish a site for the repetitive for-
mation of OH radicals. Only high affinity chelators or
some chemically similar, yet redox-inactive agents can
antagonize the formation of OH or shift the formation site
to less critical one. By virtue of similarities, zinc can
exchange copper and iron in certain binding sites and
attenuate cellular site-specific oxidative injury. The metal
is, therefore, capable of reducing postischemic injury to a
variety of tissues and organs, such as stomach, kidney,
intestine, retina, and brain (Powell
2000; Tapiero and Tew
2003).
Zinc and immunity
The profound effect of zinc on innate and adaptive
immunity is undisputable. Zinc is critical for maintaining
membrane barrier structure and function. Its deficiency
causes damage to epidermal cells and to the linings of the
gastrointestinal and pulmonary tracts, what may facilitate
the entrance of potential pathogens and noxious agents into
the body (Shankar and Prasad
1998). The first cells, which
recognize and eliminate invading pathogens, are cells of
the innate immune system, notably polymorphonuclear
cells (PMNs), macrophages, and natural killer (NK) cells.
Zinc deficiency leads to reduced PMN chemotaxis and
decreased phagocytosis, while zinc supplementation has
the opposite effect. The destruction of pathogens after
phagocytosis relies, among others, upon the activity of
NADPH oxidase, which may be inhibited by both zinc
deficiency and zinc excess. Moreover, zinc augments
monocyte adhesion to endothelial cells in vitro and affects
production of proinflammatory cytokines, such as inter-
leukins IL-1b, IL-6, and TNF-a. The element is also
involved in recognition of major histocompatibility com-
plex (MHC) class I by NK cells, and the lytic activity of
NK cells is affected during zinc depletion. In vitro,
Antioxidant and anti-inflammatory effects of zinc 15
123