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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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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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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


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


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


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


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

16 zincage rink-1

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