Zinc-altered immune function

Lothar Rink

Institute of Immunology
University Hospital
RWTH Aachen University
University Hospital Aachen
Decreased parameters of the immune
system 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)
 Contents
1. Direct effects of zinc on leukocytes

2. Modulation of the immune response by zinc

in vitro and in vivo

3. Zinc-uptake
TNF-α RT-PCR of PBMC
123bp
ladder
0 Zn Co Ni Hg LPS
β-actin
TNF-α
% of zinc-induced cytokines Cytokine production by PBMC

l
tro
on
C
Cation conentration
 Contents
1. Direct effects of zinc on leukocytes

2. Modulation of the immune response by zinc

in vitro and in vivo

3. Zinc-uptake
Cytokine concentration
Indirect T cell stimulation

γ β

Control Zinc Control Zinc

w/o with separation
separation
Inhibition of IL-1 dependent
T-cell proliferation
Inhibition of IL-1 receptor-associated
kinase activity by zinc
Zinc inhibits the IFN-γ production
in the MLC
Zinc inhibits the MLC comparable to
Cyclosporin A

1000

800
IFN-γ (pg/ml)

600

400
* * *

200

MLC MLC MLC MLC CsA

50µM zinc 100µM zinc

n = 16
Zinc intake inhibits alloreactivity in every
donor combination

1600

1400

1200
IFN-γ (pg/ml)

1000
*
800

600

400

200

before after

zinc intake

n = 15
Reconstitution of IFNα
production by zinc
 Contents
1. Direct effects of zinc on leukocytes

2. Modulation of the immune response by zinc

in vitro and in vivo

3. Zinc-uptake
Zinc uptake in peripheral blood
mononuclear cells
 fluorescence increase (% of control)

PBMC
monocytes
Zinc uptake

T cells
 Complete zinc uptake

Zinc mg/l

Control
5min 0.1 mM
1h 0.1 mM

Whole blood PBMC in SF PBMC in RPMI + FCS

Influence of zinc on B cells in vivo
B cell functions
Apoptosis Apoptosis
Normal

High
zinc
dosages
Physiological normal
Deficiency
Serum zinc concentration
Influence of zinc on monocytes in
vivo
Monocyte/Macrophage functions
Apoptosis Direct
Decreased Normal activation
Normal

High zinc dosages

Physiological above
Deficiency normal 30µM 100µM
Serum zinc concentration
 Influence of zinc on T cells in vivo
T cell functions
Apoptosis Apoptosis
Suppressed
Increased auto- and Decreased
alloreactivity Normal

High zinc dosages

Physiological above
Deficiency normal 30µM 100µM
Serum zinc concentration
Expression of hZIPs in Leukocytes

3,5

2,5

x-fold Expression
1,5

0,5

0
hZip1-THP hZip2-THP hZip3-THP hZip1-RAJI hZip2-RAJI hZip3-RAJI hZip1- hZip2- hZip3-
JURKAT JURKAT JURKAT
 Regulation of hZIPs in
THP monocytes
5

4,5

3,5

2,5
x-fold Expression

1,5

0,5

0
hZip1 hZip2 hZip3 hZip1-15 hZip2-15 hZip3-15 hZip1-30 hZip2-30 hZip3-30 hZip1-2,5 hZip2-2,5 hZip3-2,5
Zn Zn Zn Zn Zn Zn TPEN TPEN TPEN
Regulation of hZIPs in Jurkat T cells
4,5

3,5

2,5

x-fold Expression
2

1,5

0,5

0
hZip1 hZip2 hZip3 hZip1-15 hZip2-15 hZip3-15 hZip1-30 hZip2-30 hZip3-30 hZip1-1,0 hZip2-1,0 hZip3-1,0
Zn Zn Zn Zn Zn Zn TPEN TPEN TPEN
 Regulation of hZIPs in
Raji B cells
45

40

35

30

25

x-fold Expression
20

15

10

0
hZip1 hZip2 hZip3 hZip1-15 hZip2-15 hZip3-15 hZip1-30 hZip2-30 hZip3-30 hZip1-2,5 hZip2-2,5 hZip3-2,5
Zn Zn Zn Zn Zn Zn TPEN TPEN TPEN
 Conclusions

• Only zinc induces cytokine transcription

• Zinc blocks some T cell functions
• Zinc enhances monocyte response
• Zinc reconstitutes decreased IFN-α production of
elderly
• Zinc enters the cells within minutes
• Zinc transporters are different in leukocyte subsets
 Perspectives

• Zinc prophylaxis in elderly or other

zinc-deficient patients

• Zinc therapy in T cell-dependent

diseases
 Zinc Projects

Immunology Internal Medicine

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Irem Cakman Michael U. Martin
Christian Faber
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