(Journal of Leukocyte Biology. 2002;71:381-387.)
© 2002
by Society for Leukocyte Biology
The role of growth hormone in T-cell development and reconstitution
Lisbeth A. Welniak,
Rui Sun and
William J. Murphy
Laboratory of Immunoregulation, NCI-Frederick and Intramural Research Support Program, SAIC, NCI-Frederick, Frederick, Maryland
 |
ABSTRACT
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Growth hormone (GH), directly or through GH-induction of insulin-like
growth factor (IGF)-1, has been implicated in lymphocyte development
and function. Recent studies have questioned the role of GH and IGF-1
in immune responses. This review examines experimental data describing
the immunoregulatory function of GH and attempts to reconcile the
literature.
Key Words: neuroendocrine hormones • thymus • dwarf • deficiency
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INTRODUCTION
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The first studies suggesting that growth hormone (GH) may have a
role in the endocrine and immune systems occurred several decades ago
when thymic atrophy was observed in rats following hypophysectomies
(surgical removal of the anterior pituitary) [1
]. More
that 50 years later, administration of GH was used to correct
lymphocyte defects in rodents lacking the anterior pituitary through
surgical intervention or inherited defects [2
3
4
5
].
Correlative associations with low or decreasing production of GH with
thymic atrophy associated with normal aging have fueled the speculation
that correction or augmentation of GH levels could enhance immune and
particularly T-cell function.
|
GH PRODUCTION AND RECEPTOR EXPRESSION
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GH, also known as somatotropin, is a member of a family of growth
factors that includes prolactin, placental lactogens, proliferins, and
somatolactin. GH family members are secreted as 22–25 kDa monomers and
are generally not glycosylated [6
]. Circulating human GH
includes the intact molecule as well as oligomers and two-chain
isomers, a result of proteolytic cleavage. There is also a "20k"
form generated by alternative splicing that may lack some GH activities
[7
]. In the serum, GH is complexed with binding proteins
related to the GH-receptor extracellular domain [8
]. GH
is produced and stored in somatatrophs in the anterior pituitary
[9
] and is the major source of circulating hormone. The
production of GH is pulsatile, mainly nocturnal, and is controlled by
hypothalamic hormones such as GH-releasing hormone (GHRH), hypothalamic
GH release-inhibiting factor, and somatostatin. Circulating levels of
GH are highest in the immediate neonatal period, decreasing during
childhood but peaking again during puberty. GH secretion falls
precipitously during aging. GH is a diabetogenic substance, and its
secretion is decreased in obesity and rises during starvation. It has
been demonstrated that GH is produced by normal lymphocytes
[10
11
12
13
]. In humans, unstimulated peripheral blood
lymphocytes (PBL) express GH mRNA, and up to 10% of the cells secrete
biologically active protein [10
11
12
]. B cells are the
predominate source of GH mRNA, and T cells express mRNA to a lesser
extent [14
]. GH production has also been demonstrated in
splenic CD4+ T cells, B cells, and macrophages of the rat
[13
].
GH stimulates the production of insulin-like growth factor (IGF)-1,
which is responsible for many of the activities attributed to GH. GH
also has direct effects, including lipolysis [15
],
increased amino acid transport into cells, and increased protein
synthesis [16
] as well as lactogenic effects through the
engagement of the prolactin receptor [17
,
18
].
Primate GH binds tightly to GH and prolactin receptors, whereas human
prolactin can bind to the prolactin (PRL) receptor but not the
GH receptor [19
, 20
]. The murine
counterparts only bind their respective receptors. Both receptors are
members of a hematopoietin-receptor family, which is based on the
overall homology and characteristic motifs, including two cysteine
pairings and the WSXWS box in the extracellular domain. There is also
limited homology in the intracellular domain among the family members
[21
]. Like other members of the hematopoietin-receptor
family, engagement of the GH and PRL receptor activates JAK2
[22
]. The GH receptor is expressed at high levels in
liver and adipose tissues, although it can also be detected in other
tissues in rodents, including intestine, brain, testis, heart, and
skeletal muscle [8
]. Studies performed by Gagnerault and
colleagues [23
] demonstrated in mice that the GH
receptor is found on bone marrow-derived cells including CD4+CD8+ and
CD8+ thymocytes as well as CD4- and CD8- thymic cells. The receptor
is found at variable levels on all hematopoietic lineages in the
bone marrow and on subsets of B cells, CD4+ and CD8+ T cells, and
macrophages in the secondary lymphoid tissues. T-cell activation
increases the proportion of CD4+ and CD8+ splenocytes expressing the GH
receptor. The PRL receptor is also found on all GH-receptor
positive-peripheral T cells [23
, 24
]. In
humans, tonsillar B cells express GH receptors constitutively, but the
receptor was observed only on activated T cells [25
],
although another study found mRNA transcripts for GH receptors in
unstimulated peripheral blood B cell, T cells, and neutrophils
[14
]. Although the GH receptor has not been
characterized on natural killer (NK) cells, studies have shown that NK
cell numbers and activity in patients with GH deficiency are depressed,
suggesting a role for GH in NK cell biology [26
,
27
].
|
IGF-1 PRODUCTION AND RECEPTORS
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IGF-1, known as somatomedin C, is produced in high concentrations
in the liver and at lower concentrations in a variety of other tissues
in response to GH. It has been shown in man that serum concentration of
IGFs varies with age and physiologic condition. IGF-1 concentration is
low in neonates and remains low until a peak during puberty. Serum
IGF-1 along with GH decreases with advancing age. Low serum IGF-1 and
IGF-2 levels are observed in GH deficiency, and excess GH results in
elevated IGF-1 levels but normal levels of IGF-2. The major source of
circulating IGF-1 is the liver. This source participates in the
regulation of GH secretion by the pituitary, but it is not necessary
for normal growth and development [28
]. Prior to this
finding, the bi-directional interaction between the liver and pituitary
was thought to be necessary for normal growth. However, local tissue
production of IGF-1 in response to GH has been shown to be sufficient.
Similarly, although deficiency in pituitary GH may result in some
aspects of immunodeficiency, local production of GH and IGF-1 may
compensate. In the circulation, IGFs are complexed with binding
proteins [29
]. In the liver, IGF-I gene expression is
tightly regulated by GH, whereas in nonhepatic tissues, IGF-I gene
expression is regulated by tissue-specific factors in addition to GH.
Rat and human leukocytes have been shown to produce IGF-1 after in
vitro stimulation with GH [30
, 31
]. As
demonstrated in mice and man, macrophages are the primary source of
IGF-1 in leukocytes [32
, 33
]. Thymic
epithelial cells also produce IGF-1 in response to GH, which may result
in an autocrine loop because IGF-1 stimulates cell growth of the same
cells [34
35
36
]. Cells of the bone marrow
microenvironment also express IGF-1 and its receptor
[37
38
39
].
The IGF-1 receptor is a member of the tyrosine-kinase growth-factor
receptors and is highly homologous to the insulin receptor
[40
, 41
]. The receptor is a heterotetramer
composed of two 
and two ß subunits. IGF-1 receptors have been
shown on the majority of B cells, NK cells, and monocytes, as well as
erythrocytes [42
43
44
45
46
47
]. Studies differ regarding the
percentage of T-cell populations that express IGF-1 receptors
[42
, 45
, 48
], although the
number of receptors can be influenced by the activation state of the
cell [46
, 47
]. Rat and human leukocytes
have been shown to produce IGF-1 after in vitro stimulation with GH
[30
, 31
]. In the thymus, CD4-CD8-
thymocytes express the highest level of IGF-1 receptors, followed by
CD4+CD8+ thymocytes; lower levels of receptor expression were observed
on single-positive cells [49
, 50
]. Thus, in
determining the role of GH in immune-system development and function,
direct effects by GH and indirect effects through IGF-1 on particular
cell types must also be taken into consideration.
|
GH AND IMMUNE FUNCTION: EARLY STUDIES
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One of the earliest associations linking GH with the thymus was
the observation that thymic atrophy with aging correlated with GH-level
decline. Early studies examining the role of GH on immune parameters
used in vitro assays assessing the effects of GH on immune function or
in vivo models of GH deficiency that occurred via surgical manipulation
(hypophysectomy) or through examination of neuroendocrine
hormone-deficient dwarf mice. A variety of in vitro studies have
demonstrated that exogenous GH could improve a variety of immune
functions including B-cell responses and antibody production
[51
, 52
], NK activity [53
],
macrophage activity [54
55
56
], and T-cell function
[53
]. In vitro chemotaxis of monocytes as well as
increases in respiratory burst activity were demonstrated after GH
exposure [57
, 58
]. NK cell-killing activity
was also described as increased after GH treatment in vitro, although
the mechanism remains speculative, because PRL has also been shown to
increase NK function [59
], and human GH can exert
prolactinogenic effects [17
, 60
]. GH has
been shown to augment immunoglobulin production in vitro, which may
also be in part a result of IGF-1, which has direct effects on B cells
in vitro [61
]. In vitro studies have also shown that GH
could enhance human and murine T-cell function, as reflected by
proliferation and antigen-specific responses [62
].
Therefore, these in vitro studies indicate that GH can stimulate a
variety of immune parameters by direct and indirect mechanisms
(Fig. 1
). However, many in vitro studies use fetal bovine serum in the
media, which contains bovine IGF-1 and other hormones. This may result
in the underestimation or overestimation of the effects of exogenous
growth factors such as the GH used in the assay. In vivo studies of GH
deficiency also suggested a pivotal role of GH in immune development,
because initial characterization of Ames (df/df) and
Snell-Bagg (dw/dw) dwarf mice indicated severe immune
deficits, and some studies observed that the mice died prematurely,
presumably from infection [63
]. Both these mice fail to
express the pit-1 gene product and lack developed
somatotrophs (which produce GH), lactotrophs (which produce prolactin),
and thyrotrophs (which produce thyroid-stimulating hormone)
[64
65
66
], although the animals are not totally devoid of
these hormones, because not all nonpituitary sources of prolactin and
GH are under pit-1 control. Later studies using these mice
in conventional animal facilities that were specific and pathogen-free
suggested that the early death demonstrated by these mice was a result
of infectious agents in the facility, because again, no premature
deaths were shown [67
68
69
]. These studies clearly
demonstrate the importance of housing conditions in determining the
role of GH on immune parameters as well as effects of the aging process
in general. Although these studies suggested that GH and possibly other
neuroendocrine hormones could play a role in modulating immune
development and function, they did not demonstrate an obligatory role
for these hormones in immune function. There have been studies
indicating that dwarf mice had impaired B-cell development and thymic
hypoplasia as well as myeloid deficits [4
]. Studies by
Dorshkind and Horseman [70
] carefully assessed the
immune competence of the various hormone-deficient mice and found that
T-cell function and development appeared normal with the exception of a
B-cell abnormality affecting the pre-B-cell stage in development. This
defect could be reversed by treatment of the mice with thyroxine,
suggesting that neuroendocrine hormones could play an obligatory role
in immune development [71
]. Indeed, this deficit in
B-cell progenitors may have influenced the expansion in T cells
demonstrated in dwarf mice and may account for the increases shown in
the aged mice [67
]. However, the role of GH in T-cell
development, particularly in the thymus, remained elusive. GH
deficiency in man is not associated with gross thymic defects or T-cell
deficiencies. Administration of GH to dwarf mice could restore thymic
cellularity in dwarf mice, suggesting that although GH may not be an
obligate T-cell growth factor, it could exert thymopoietic effects in
vivo. Also complicating interpretation of the dwarf data was the
observation that the time of weaning was critical in affecting the
extent of thymic hypoplasia, suggesting that potential thymopoietic
factors could be present in maternal milk that could compensate for the
lack of GH or prolactin in these mice [72
].
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Figure 1. The role of GH, IGF-1, and somatostatin, an inhibitor of GH production,
on immune development. GH and IGF-1 have been shown to promote
hematopoiesis, including B-cell precursors, myeloid, erythroid, and
megakaryocytic lineages. NK cell development may also be promoted by
GH. GH and IGF-1 can promote T-cell development in the thymus. GH and
IGF-1 promote T-cell chemotaxis and may play a role in T-cell precursor
immigration into the thymus and lymphocyte circulation into and between
secondary lymphoid tissues. GH and IGF-1 may also promote
antigen-specific immune function within the lymphoid tissues, and
somatostatin may inhibit these functions. Those effects of GH, IGF-1,
or somatostatin that have not yet been proven are indicated with a
question mark (?).
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RECONCILIATION OF THE GH LITERATURE CONCERNING THE ROLE OF GH
ON THE THYMUS
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The conflicting data concerning the extent of thymic hypoplasia
and the demonstrated susceptibility of these mice to infection led us
to the hypothesis that the role of neuroendocrine hormones (i.e., GH)
in the immune response may be in the protection from stress
[70
, 73
]. The thymus is exquisitely
sensitive to glucocorticoids induced by stress. Therefore, multiple
variables need to be taken into consideration when evaluating in vivo
data concerning the role of hormones on immune parameters. These
include the health status of the mouse colony [pathogens such as
helicobacter and orphan parvoviruses can still be present in specific
pathogen-free (SPF) colonies and manifest themselves during
immune-deficiency states]; housing conditions (males often fight when
housed together, resulting in injury and stress); diet; mouse strains
used; influence of background genes on immune parameters; age and sex
of the mice used; and whether the mice were under "resting" or
unmanipulated conditions or whether they were placed under stress
situations (i.e., receiving chemotherapy, tumors, etc.). All of these
variables can markedly affect outcome with regard to effects on immune
parameters. Dwarf mice present an excellent example about how the
conclusions reached regarding the role of GH on immune parameters were
critically dependent on the status of the mouse colony. Early studies
demonstrated that dwarf mice succumbed to a "wasting disease,"
presumably infection. These studies suggested that GH played a critical
role in immune function. As mouse colonies became SPF, the dwarf mice
were no longer shown to present with this wasting disease and displayed
modest perturbations of immune parameters [67
68
69
].
Indeed, a recent study demonstrated that dwarf mice actually had longer
life spans compared with normal littermate controls and also had
improved T-cell functions as they aged [74
]. This study
would suggest that GH played a role in promoting aging and potentially
inhibiting T-cell function with age. Thymic function was not assessed
in this study, and only memory T cells, not naïve T cells, were
increased [74
]. However, before extrapolating these data
to man, the model used and the variables associated with in vivo
studies must be taken into consideration. These studies used resting
dwarf mice in an SPF colony where exposure to infectious agents is
minimal. Reconciling information derived from mice under these
conditions with the human situation is difficult to ascertain. Therein
lies a potential problem—making broad conclusions concerning
immunological effects when using inbred mice under SPF conditions.
Thus, depending on the conditions of the colony, the dwarf mice could
die early from infection versus controls, or they could actually living
longer than controls. This recent study also does not resolve the
differences in results demonstrated between two laboratories
characterizing the thymus of these mice when younger. It has been shown
that the time of weaning can affect the extent of thymic deficiency in
these mice [72
], but the mice in the two laboratories
were weaned at the same time. If the colonies were constant with regard
to being pathogen-free, it was possible that housing conditions may
have influenced thymic outcome. Although female mice, which do not
normally engage in observable fighting behavior, were used in the
studies, it was possible that the dwarf mice were "stressed" by
being in the presence of the normal-sized littermates, because one
group housed them with littermates, and the other did not. Therefore,
an experiment was performed in which dwarf mice were housed by
themselves or with their normal-sized littermates. The results
indicated that simply placing the dwarf mice with their normal-sized
littermates had a dramatic effect on their thymus (Table 1
; and unpublished results). These results indicated that GH was not
an obligate T-cell development factor but instead was involved in
circumventing thymic responses to stress situations (i.e.,
corticosteroid release). Importantly, the administration of GH could
reverse this susceptibility [73
]. In fact, IGF-1 and GH
have been shown to partially inhibit dexamethasone-induced apoptosis in
CD4+ T cells [75
]. It remains to be determined if an
increased susceptibility to stress was a result of the absence of GH or
if this phenomenon will occur in stressed mice with normal GH levels.
It is also still not known whether GH provides a direct protective
effect on the thymocytes or works indirectly through IGF-1, which is
also known to provide antiapoptotic effects [76
,
77
]. Alternatively, GH could promote the production of
interleukin (IL)-7 or SCF from the thymic epithelial cells (Fig. 2
). This suggests that the role of GH in the immune response may be
a means to counteract the immunosuppressive effects of stress and could
be of potential clinical use in that regard. Thus far, very few agents
have been shown to exert thymopoietic effects in vivo. The need for the
thymus to repopulate the peripheral T-cell pool in the adult has been
required only recently with the advent of myeloablative therapy during
bone marrow transplantation and in AIDS. Because patients in both of
these instances are under stress situations, GH may be of use to
augment thymic recovery in the adult.
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Figure 2. The role of GH and IGF-1 on the thymus and thymocyte development. GH
and IGF-1 are produced in the lymphoid tissue, which may result in
paracrine stimulation of T-cell development. However, the primary
source of circulating GH is the anterior pituitary, which is controlled
through a negative-feedback loop involving IGF-1 production in the
liver. Glucocorticoids can induce thymic atrophy. The mechanism by
which GH protects the thymus under stress conditions is not known.
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EFFECTS OF GH ON PERIPHERAL T-CELL FUNCTION
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GH appears to affect T-cell function by promoting thymic function
and progenitor survival as well as promoting T-cell function in the
periphery. GH and IGF-1 have been shown to increase T-cell functions in
vitro [62
, 78
79
80
]. GH receptors have been
shown to be present on T cells, although the expression of these
receptors on T-cell subsets (memory vs. naïve) or as the
individual ages has not been ascertained. Another important question is
the mechanism by which GH works on the T-cell response. Does GH promote
the proliferation, activation, or survival of the T cell? These
parameters have yet to be addressed adequately. GH has been used as an
adjuvant to promote cell-mediated responses to various pathogens
[53
]. However, it is not known if these effects were
directly a result of GH binding on T cells or indirect effects by
stimulation of monocytes and antigen-presenting cells, because both are
affected by GH in vitro [55
, 57
,
58
, 81
82
83
]. Additionally, when human GH is
used, it is possible that binding the prolactin receptor may account
for the immunostimulatory effects, because prolactin has also been
shown to promote T-cell function in vitro and in vivo
[84
85
86
87
]. Another means by which GH can promote T-cell
responses is through effects on lymphocyte trafficking and
recirculation (Fig. 1)
. GH administration has been shown to promote
human T-cell trafficking in immunodeficient mice [88
].
These results suggest that clinical use of GH to promote T-cell
responses may result with thymopoietic effects as well as peripheral
T-cell effects being generated. It will be of interest to ascertain if
GH can prevent apoptosis of lymphocytes and promote memory T-cell
survival. An important caveat that needs to be addressed is the
potential role of GH in promoting autoimmunity and potentially
disregulating immune responses during chronic inflammation states. It
will be of interest to ascertain the effects of GH administration in
autoimmune-prone strains of mice or in mice receiving chronic
inflammatory stimuli.
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GH AND BONE MARROW TRANSPLANTATION
|
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The immune system is part of the hematopoietic system in which all
lymphoid cells have arisen from a hematopoietic pluripotential stem
cell (Fig. 1)
. GH has been shown to promote hematopoietic growth in
vitro [89
]. One possible means by which it could affect
immune-system reconstitution and development may be by promoting
hematopoietic growth in vivo. We wanted to ascertain the effects of GH
on hematopoietic reconstitution following syngeneic bone marrow
transplant (BMT) in mice. Mice were prepared with a
myeloablative dose of whole-body irradiation prior to a syngeneic BMT,
followed by human GH administration at doses that did not promote
weight gain. Significant effects on multilineage hematopoietic
reconstitution were observed [89
], suggesting that GH
can be of use to promote myeloid recovery after BMT. These results, in
combination with studies of T-cell development and immune function
described above, demonstrate that GH can exert effects on immune and
myeloid parameters in vivo at doses that do not exert readily
observable anabolic effects. Thus, GH is pleiotropic in its effects in
vivo, affecting numerous immune and myeloid lineages. Many of the
observed effects on myeloid and lymphoid reconstitution may be assumed
to be because of GH induction of IGF-1, given that studies have
demonstrated that IGF-1 administration can exert effects on
hematopoiesis and thymic reconstitution [50
,
90
]. However, administration of prolactin also promotes
hematopoietic recovery and stimulates lymphoid function
[91
, 92
]. Because human recombinant GH acts
through the GH and PRL receptors and stimulates production of IGF-1,
additional benefit may be provided by the use of GH over PRL or IGF-1.
The use of a hormone-like GH does not appear to exert the same
magnitude of effects observed when a cytokine [i.e., granulocyte
colony-stimulating factor (G-CSF) or granulocyte-macrophage CSF
(GM-CSF)] is administered, but it appears more diverse in its outcome.
This augmentation of hematopoiesis by GH may also represent another
means by which GH can promote thymic recovery in that increased
production of pro-T cells may occur to seed the thymus (Fig. 1)
.
|
POTENTIAL, CLINICAL USE OF GH TO PROMOTE IMMUNE RECONSTITUTION;
OTHER CONSIDERATIONS
|
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Although GH may indeed be of potential clinical use to promote
T-cell reconstitution, other considerations need to be addressed. The
effects of IGF-1 as a result of GH administration on tumor growth may
result in higher relapse rates if GH is used to accelerate
reconstitution in cancer patients receiving a BMT. Another important
consideration is the end-point used in a clinical study with GH. Gross
effects on T-cell counts may not be affected, and it may be critical to
monitor development of naïve T-cell pools in the periphery to
detect any effects of GH treatment. It is also possible that simply
administering GH alone cannot restore thymic function in elderly
individuals. We need more research to understand the aging process of
the thymus and the role of GH in protecting the thymus from stress.
Thus, the data from pituitary-deficient and hormone or hormone-receptor
animals and man suggest that GH is not an obligate factor in T-cell or
other immune-cell development. However, although GH is not necessary
for normal development, it does appear that GH can enhance T-cell
survival and thymic function in times of stress and may therefore be of
use in immune-deficiency states to promote immune development and
function.
|
ACKNOWLEDGEMENTS
|
|---|
This project has been funded in whole or in part with federal funds
from the National Cancer Institute, National Institutes of Health,
under Contract No. NO1-CO-12400. The content of this publication does
not necessarily reflect the views or policies of the Department of
Health and Health Services, nor does mention of trade names, commercial
products, or organizations imply endorsement by the U.S. Government.
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FOOTNOTES
|
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Correspondence: William J. Murphy, Ph.D., Intramural Research
Support Program, SAIC, Bldg. 567, Room 210, Frederick, MD 21702.
E-mail: murphyw@ncifcrf.gov
Received October 24, 2001;
revised December 4, 2001;
accepted December 5, 2001.
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ABSTRACT
INTRODUCTION
