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Zinc-altered immune function
Lothar Rink
Institute of ImmunologyUniversity Hospital
RWTH Aachen University
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University Hospital Aachen
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Decreased parameters of the immunesystem during zinc deficiency
Thymocyte and T cell counts and proliferation
Delayed-type hypersensitivity reaction
Cytotoxic (CTL) and T-helper (Th) cell-functions
Antibody production
NK cell activity
Macrophage functions (phagocytosis, killing)
Neutrophil functions (oxygen burst,chemotaxis)
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Contents1. Direct effects of zinc on leukocytes
2. Modulation of the immune response by zinc
in vitro and in vivo
3. Zinc-uptake
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TNF- RT-PCR of PBMC
-actin
TNF-
123bpladder
0 Zn Co Ni Hg LPS
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Cytokine production by PBMC
C o n t r
o l
Cation conentration
% o
f z i n c -
i n d u c e
d c y
t o k i n e s
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Contents1. Direct effects of zinc on leukocytes
2. Modulation of the immune response by zinc
in vitro and in vivo
3. Zinc-uptake
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Indirect T cell stimulation
Control Zinc Control Zinc
w/oseparation with separation
C y t o
k i n e
c o n c e n t r a
t i o n
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Inhibition of IL-1 dependentT-cell proliferation
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Inhibition of IL-1 receptor-associatedkinase activity by zinc
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Zinc inhibits the IFN- production
in the MLC
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Zinc inhibits the MLC comparable toCyclosporin A
MLC MLC MLC MLC CsA50M zinc 100M zinc
I F N -
( p g / m
l )
0
200
400
600
800
1000
***
n = 16
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Zinc intake inhibits alloreactivity in everydonor combination
before after
zinc intake
I F N -
( p g
/ m
l )
0
200
400
600
800
1000
1200
1400
1600
*
=
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Reconstitution of IFN production by zinc
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Contents1. Direct effects of zinc on leukocytes
2. Modulation of the immune response by zinc
in vitro and in vivo
3. Zinc-uptake
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Zinc uptake in peripheral blood
mononuclear cells
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Zinc uptake
PBMC monocytes T cells f l u o r e s c e n c e
i n c r e a s e
( %
o f c o n
t r o l )
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Complete zinc uptake
Zinc mg/l
Whole blood PBMC in SF PBMC in RPMI + FCS
Control
5min 0.1 mM
1h 0.1 mM
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Influence of zinc on B cells in vivo
Apoptosis Apoptosis
Deficiency
Normal
Physiological normal
Highzincdosages
B cell functions
Serum zinc concentration
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Influence of zinc on monocytes in
vivo
Deficiency
Physiologicalnormal
High zinc dosagesabove
Monocyte/Macrophage functions
Serum zinc concentration
Normal
ApoptosisDecreased
30 M 100 M
NormalDirect
activation
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Influence of zinc on T cells in vivo
DeficiencyPhysiologicalnormal
High zinc dosagesabove
T cell functions
Serum zinc concentration
Normal
Apoptosis Apoptosis
Increased auto- andalloreactivity
Decreased
Suppressed
30 M 100 M
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Expression of hZIPs in Leukocytes
0
0,5
1
1,5
2
2,5
3
3,5
hZip1-THP hZip2-THP hZip3-THP hZip1-RAJI hZip2-RAJI hZip3-RAJI hZip1-JURKAT
hZip2-JURKAT
hZip3-JURKAT
x-fold Expression
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Regulation of hZIPs inTHP monocytes
0
0,5
1
1,5
2
2,5
3
3,5
4
4,5
5
hZip1 hZip2 hZip3 hZip1-15Zn
hZip2-15Zn
hZip3-15Zn
hZip1-30Zn
hZip2-30Zn
hZip3-30Zn
hZip1-2,5TPEN
hZip2-2,5TPEN
hZip3-2,5TPEN
x-fold Expressio n
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Regulation of hZIPs in Jurkat T cells
0
0,5
1
1,5
2
2,5
3
3,5
4
4,5
hZip1 hZip2 hZip3 hZip1-15Zn
hZip2-15Zn
hZip3-15Zn
hZip1-30Zn
hZip2-30Zn
hZip3-30Zn
hZip1-1,0TPEN
hZip2-1,0TPEN
hZip3-1,0TPEN
x-fold Expressio n
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Regulation of hZIPs inRaji B cells
0
5
10
15
20
25
30
35
40
45
hZip1 hZip2 hZip3 hZip1-15Zn
hZip2-15Zn
hZip3-15Zn
hZip1-30Zn
hZip2-30Zn
hZip3-30Zn
hZip1-2,5TPEN
hZip2-2,5TPEN
hZip3-2,5TPEN
x-fold Expressio n
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Conclusions
Only zinc induces cytokine transcription Zinc blocks some T cell functions
Zinc enhances monocyte response Zinc reconstitutes decreased IFN- production of
elderly Zinc enters the cells within minutes
Zinc transporters are different in leukocyte subsets
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Perspectives
Zinc prophylaxis in elderly or other zinc-deficient patients
Zinc therapy in T cell-dependentdiseases
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Zinc Projects
Immunology Internal Medicine Nele Wellinghausen Burkhard KreftClaudia MetzPhilip Gabriel PharmacologyIrem Cakman Michael U. Martin
Christian Faber Klaus-Helge Ibs Gerontology
Hajo Haase Rudolf-M. Schtz