Zinc and Thymulin

Zinc and Thymulin
MIREILLE DARDENNE l , ANANDA PRASAD 2 , and JEAN- FRAN<;OIS BACH l

1 INSERM U25 and CNRS UA122, Paris, France
2 Wayne State University School of Medicine, Detroit, MI 48201, USA
ABSTRACT
Thymulin is a thymic hormone produced by thymic epithelial cells (TEC) known to induce
intra- and extra thymic T cell differentiation. It is a nonapeptide whose biological activity and
antigenicity depend upon the presence of zinc, which also induces conformational changes in
the molecule as demonstrated by RMN studies. The presence of zinc and metallothionein have
been demonstrated with TEC which produce the peptide, suggesting that the molecule is
secreted in its active zinc-containing form.
In order to define the zinc/thymulin relationship, we studied various models of mild zinc
deficiency in humans. First, we showed that serum thymulin activity was decreased as a result
of zinc deficiency, and was corrected by in vivo and in vitro zinc supplementation, suggesting
that this parameter could be a sensitive indicator of zinc deficiency in humans. Secondly,
these observations, when considered together with the parallel variations seen in T-cell
subpopulations and lymphokine production, could provide a possible explanation of the role
of zinc on T cell functions.
Key words = Zinc - Thymulin - Thymic function - Zinc deficiency.
INTRODUCTION
It is now widely accepted that the trace element zinc exerts a powerful and apparently specific
influence on the thymus, on T lymphocytes and on cellular immunity, resulting in a strong
immune modulatory activity on cell-mediated responses, in both human and animal systems
(Bach, 1981 ; Good, 1981 ; Prasad, 1985).
It is apparent that Zn2+ deprivation induces a marked thymic atrophy the effects of whcih
closely resemble those of thymectomy: either natal thymectomy or young adult thymectomy
when performed in adulthood (Nash et aI, 1979).
The mechanisms underlying the early thymic atrophy observed in zinc-deprived mice are of
considerable interest. One hypothesis is that the rapidly dividing lymphocytes present in the
thymus are particularly sensitive to the abnormal function of zinc dependent enzymes
necessary for lymphocyte proliferation. Alternatively, several investigators have evoked the
possibility that the epithelial function of the thymus may be specifically altered by such
nutritional deficiency of zinc (Chandra et ai. 1980; Iwata et ai. 1979). They reported that a
Zn-deficit induces a significant lowering of the serum level of the thymic hormone, thymulin
(previously called serum thymic factor (FTS), both in animal models such as mice and rats
and in patients with common variable immunodeficiency (Cunningham-Rundles et aI., 1981)
chronic renal failure (Travaglini et al. 1989) or sickle cell anaemia (Prasad et al. 1988).
H. Tomita (ed.), Trace Elements in Clinical Medicine

© Springer-Verlag Tokyo 1990
178
Moreover, Zn administration restored normal hormone levels. Data from our laboratory
favored the view that thymulin was directly dependent on zinc, a finding which which could
explain many of the observations reported above (Dardenne et al,1982). In the present review
we shall focus our attention on the presence of zinc within the thymus and its relationship
with the biological activity and secretion of thymulin, a chemically defined, zinc dependent
thymic hormone, which by itself is able to induce T-cell markers and functions our immature
lymphocytes.
PRESENCE OF ZINC WITHIN THE THYMUS
Direct evidence for the presence of zinc within the thymus has come from our previous
observations using electron microprobe analysis on ultrathin sections of mouse thymus. Using
this technique we detected zinc inside cytoplasmic vacuoles of thymic epithelial cells (TEC),
and further experiments demonstrated that this metal can be accumulated within these
subcellular structures in thymuses from mice previously injected with zinc chloride (Nabarra
et al. 1984). These vacuoles were also shown to contain thymulin.
These data clearly indicate that zinc could be stored within TEC by some specific mechanism.
One hypothetical candidate for a role in the intra-thymic storage of zinc could be
metallothionein. This low molecular weight protein has a high cysteine content and is known
to bind, with high avidity, classe IT B transitional metals, namely zinc, cadmium and copper
(Kai et al. 1980). Moreover, it has been previously shown that it is highly expressed in cells
that can store zinc (Danielan et al. 1982). These findings led us to look for metallothionenin
within thymus, and we demonstrated by immunocytochemical means the presence of this
protein in thymic epithelial cells both in vivo and in vitro (Savino et al. 1984). By in vitro
experiments we showed that zinc-loaded metallothionein released zinc which was eventually
trapped by thymulin. In this respect our findings support the notion that metallothionein can
function as a zinc acceptor/donor.
PRESENCE OF ZINC IN BIOLOGICALLY ACTIVE THYMULIN
General aspects of thymulin
Thymulin is a thymic hormone isolated from serum, which has been characterized by its
capacity to induce T cell markers on T cell precursors (Bach, 1983).
Thymulin is absent in the serum of nude or thymectomized (Tx) mice and reappears after
thymus grafting. Chemical analysis showed that it is a peptide of molecular weight 847.
Based on aminoacid analysis and sequence studies on the intact peptide and on the peptide
treated with proteolytic enzymes by Edman's method, the aminoacid sequence proposed for
thymulin is the following :
< Glu-Ala-Lys-Ser-Gln-Gly-Gly-Ser-Asn-OH.
There is no apparent species specificity, as the aminoacid analysis of calf and human thymulin
is identical to that of porcine thymulin.
On the basis of this sequence, a peptide has been synthesized according to two methods, using
solid-phase synthesis (Merrifield's technique) and classical solution methods by Bricas et al
(1972) and P. Lefrancier et al (1984). The synthetic material showed full biological activity
and chromatographically displayed characteristics identical to those of natural thymulin in
several chromatography systems.
Data obtained in our laboratory demonstrated that thymulin binds to high affinity receptors
(Pie au et al. 1980), induces several T cell markers and promotes T-cell functions including
allogeneic cytotoxicity, suppressor function and interleukin-2 production (Bach et al. , 1980).

Zinc and Thymulin

Uploaded by

Copyright:

Available Formats

Zinc and Thymulin

Uploaded by

Document Information

Original Description:

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Zinc and Thymulin

Uploaded by

Copyright:

Available Formats

Zinc and Thymulin

MIREILLE DARDENNE l , ANANDA PRASAD 2 , and JEAN- FRAN<;OIS BACH l

Key words = Zinc - Thymulin - Thymic function - Zinc deficiency.

H. Tomita (ed.), Trace Elements in Clinical Medicine

PRESENCE OF ZINC WITHIN THE THYMUS

PRESENCE OF ZINC IN BIOLOGICALLY ACTIVE THYMULIN

General aspects of thymulin

You might also like