Table Of ContentGrowth Hormone
Scott Chappel1 and William Murphy2,*
1Serono Corp., 100 Longwater Circle, PO Box B, Norwell, MA 02061, USA
2Transplantation Biology Section, SAIC Frederick, Building 567, Room 210 PO Box B,
Frederick, MD 21702-1201, USA
*corresponding author fax: 301-846-6641, e-mail: [email protected]
DOI: 10.1006/rwcy.2000.03012.
SUMMARY have autocrine/paracrine mechanisms of action. As
a result of molecular analysis, the genes for GH and
its receptor have been classified as members of the
Growth hormone (GH), while primarily noted for its
hematopoietic growth factor/receptor superfamily
anabolic effects, has also been demonstrated to have
(Hooghe et al., 1993). Despite literature to support
effects on immune cell development and function.
an effect of GH upon immune function, there are no
ReceptorsforGHhavebeenfoundtobepresentona
convincing data as to its significance or relevance as
variety of immune cell types and numerous effects on
a hematopoietic or immunomodulating agents in
immune cell functions have been reported. With the
humans. This review will summarize the biological
advent of recombinant material, it has become pos-
actions of GH as they relate to the immune system
sible to delineate the effects of GH under more
andconsidertheclinicalutilityofGHasanimmuno-
stringent conditions. However, GH may exert many
modulating agent.
of its effects indirectly through the induction and
release of IGF-1. In addition, many of the immune
effects ascribed to GH in immune system develop- Main activities and
ment and function have utilized neurendocrine
pathophysiological roles
hormone-deficient dwarf animals, which are deficient
in hormones other than GH, making interpretation
Communication between Organ Systems
concerning the role of GH in immune development
and function difficult. In addition, human GH can Interactions between organ systems are essential for
bind the prolactin receptor. Recent data suggest that survival of all species. When critical information is
GH may have effects on immune cell function under received by one system, it is relayed to others to
periods of stress, either directly or through IGF-1, ensure and coordinate optimal responses. Many
and may work in concert with other cytokines. interactions have been described between the endo-
crine and immune systems (Weigent and Blalock,
1987; Berczi, 1994; Weigent, 1996).
Productsof the immune system have a direct effect
BACKGROUND
upon endocrine function. Cytokines such as IL-1,
IL-6,IFN(cid:13),andTNFarereleasedbyimmunecellsin
Discovery
response to an invading pathogen. Many of these
acute stress cytokines have been shown to induce the
Growth hormone (GH) has long been considered a release of pituitary hormones, including prolactin,
pleiotropic molecule. Its ability to stimulate the ACTH, and GH (Besedovsky and Del-Rey, 1996).
growth and differentiation of muscle, bone, and Thus, when the immune system reacts to an acute
cartilageiswellknown(DanielsandMartin,1991).In stimulus, a portion of that response involves the
addition to the pituitary gland, GH is synthesized release of hormones, including GH.
within many other tissues, including the hematopoie- Products of the endocrine system also affect the
tic system (Clark, 1997). This suggests that it may activity of immune cells. Stressful situations elicit the
252 Scott Chappel and William Murphy
release of adrenal glucocorticoids, which are potent occur solely by a decrease in somatostatin tone.
inhibitors of the immune system. Pituitary GH is Hypothalamic GHRH is required to stimulate each
also released duringstress and influences the immune GH pulse (Ocampo-Lim et al., 1996).
system in many species (Berczi, 1994; Blalock and
Weigent, 1994; Besedovsky and Del-Rey, 1996). The Classical GH/IGF-1 Axis
Immune cells themselves appear to produce specific
The growth hormone/insulin-like growth factor
endocrine hormones, including GH (Weigent et al.,
(IGF-1)axishasbeenwellstudiedandplaysacritical
1988; Sabharwal and Varma, 1996; Wu et al., 1996),
role in growth and development of many different
prolactin (Gala, 1991; Kooijman et al., 1996) and
organ systems within the body. Growth hormone
their receptors. The capacity of immune cells to
does not act alone to stimulate mitogenesis and
respondtopituitaryGHandproduceitlocallyargues
differentiationinalltissues.SpecificreceptorsforGH
for a role of that hormone in normal immune
are found on the liver and following GH receptor
function.
activation, hepatocytes produce IGF-1. IGF-1 con-
sistsof70aminoacidsandiscarriedinthecirculation
Neural Regulation of Pituitary
as a protein complex. IGF-1 is also produced locally
GH Biosynthesis and Release
by a number of other tissues (Daniels and Martin,
The hypothalamus receives and integrates neural 1991). Both GH and IGF-1 exert growth-promoting
and humoral information from the internal and and metabolic effects on many different tissues
external environment. Following integration of that including the immune system.
information, the hypothalamus initiates the body’s
response. Often, that response involves the secretion
of hormone, such as GH. Due to its many metabolic GENE AND GENE REGULATION
actions, the release of GH is very tightly regulated
(Thorner et al., 1997). Specifically, two hypothalamic Accession numbers
peptides, GHRH and somatostatin (SRIF), are
involved in the control of GH secretion (Figure 1).
GenBank:
GHRH stimulates GH biosynthesis and release from
Growth hormone gene: J00148, K00612 (Martial
the pituitary (Frohman et al., 1992). GH exerts a
et al., 1979)
negative feedback on future GH secretion by de-
Growth hormone locus: J03071 (Chen et al., 1989)
creasing the production of additional GHRH and its
receptor(Frohmanetal.,1992;Kamegaietal.,1998).
GH also increases the activity of SRIF neurons in Chromosome location
the hypothalamus to inhibit its own secretion (Zheng
et al., 1997). SRIF inhibits GH release from the
The growth hormone gene is a member of the four
pituitary. Following inhibition of GH pulses, soma-
helical bundle hematopoietic gene superfamily that is
tostatin tone gradually declines (Thorner et al., 1990)
comprised mostly of cytokines and hematopoietic
and pulses of GH are reinitiated. GH pulses cannot
growth factors. The human chromosomal growth
hormone locus has evolved as a series of gene dupli-
cations and consists of a cluster of five genes that
Figure 1 Circuit diagram of
haveapproximately95%sequenceidentity.Thisgene
pituitary GH neuroendocrine
cluster spans 47kb on chromosome 17(q22–q24).
control and feedback.
DNA sequencing of the GH locus has revealed the
presenceofhGH-N(ormal)whichistranscribedinthe
GRF SRIH pituitaryandinthelymphoidandmyeloidfamiliesof
Hypothalamus
cells (Binder et al., 1994; Palmetshofer et al., 1995;
RohnandWeigent,1995).Fourothergeneshavealso
+ – been identified (hCS-L, hCS-A, hCS-B, and hGH-
Pituitary V(ariant)). These four genes are expressed primarily
in the placenta.
ThehGH-Ngeneisinterruptedbyfourintervening
GH
sequences that have different splice sites. These
Peripheral sites
differences in splice sites allow for the generation of
hGH of different sizes found within the normal
Metabolic
IGF-1 pituitary gland (DeNoto et al., 1981). Splice variants
effects
Growth Hormone 253
have also been described in the other four transcripts PROTEIN
within the placenta (MacLeod, et al., 1992).
Accession numbers
Relevant linkages
Human growth hormone: NM000515
The five GH locus genes plus the thyroid hormone
receptorinteractingprotein(TRIP-1)areallfoundon
the same chromosome in the human, pig, and rat Description of protein
genome and may be physically linked. There is also a
physical linkage to the CD79b gene which is B cell
Growthhormoneisapolypeptideof191aminoacids.
specific (Bennani-Baiti et al., 1998).
It is a member of a class of hematopoietic growth
factors that possess an antiparallel four (cid:11) helix
Regulatory sites and corresponding bundle fold. Proteins of the hematopoietic growth
transcription factors factor superfamily, such as GH, bind to specific
receptors that are single pass, transmembrane recep-
tors from class 1 of the hematopoietic receptor
Tissue specificity of expression is provided by pro-
superfamily.
moter regions found upstream of coding sequences.
The ligand has also been co-crystallized with its
The pituitary-specific transcription factor, POU1F1
receptor (Somers et al., 1994). High-resolution muta-
(the human homolog of murine pit-1/GHF-1) regu-
tional and structural analysis of GH have provided a
lates the expression of pituitary GH, prolactin, and
great deal of information about the ligand’s binding
thyroid-stimulating hormone through binding to
to its receptor. hGH binds to hGH receptor on cell
specific regions of the promoters of these genes (Li
membranes through site 1 and subsequently forms
et al., 1990). GHF-1/Pit-1 binds the 50 flanking DNA
a dimer by binding a second monomeric receptor
of the GH gene at two sites: (cid:255)96/(cid:255)70 and (cid:255)134/
through site 2. Dimerized receptors are able to inter-
(cid:255)106. GHF-1 transcription is autoregulated and is
actwithintracellularcomponentstotransmitasignal
also affected by factors that control cAMP levels
(Figure 2) (Wells et al., 1993).
within cells, such as GH-releasing hormone binding
to its receptor. Upregulation of GHF-1 expression
induces an increase in the rate of transcription of the
GH gene. Mutations of the pit-1 gene are responsible Discussion of crystal structure
for the syndrome of combined pituitary hormone
deficiency (Radovick et al., 1992). Pit-1 gene expres- The crystal structure of hGH has been reported
sion is also found in lymphoid and thymic cells that (Ultsch et al., 1994).
express GH (Delhase et al., 1993; Chen et al., 1997;
Kooijman et al., 1997a, 1997b).
Thyroid hormone also upregulates GH gene
expression. The TH receptor is part of the nuclear Figure2 GHinducesdimerization
receptor superfamily and when occupied, binds to of its receptor in GH responsive
GHpromotersequencesatitsnowwell-characterized cells which stimulates intracellular
consensus sequence. The GH gene also contains signaling.
upstream binding sites for the glucocorticoid recep-
tor. Two receptor binding sites have been identified,
GH
oneat(cid:255)290bpandanotherat+251bp(Eliardet al., responsive GH
cell
1985). Glucocorticoids have been shown to rapidly
increase accumulation of GH mRNA. Retinoic acid
has also been shown to induce the expression of the
GH gene. The GH promoter contains a hormone GH
responsive
response element that binds TR/RXR and RAR/ cell
RXR heterodimers located close to two binding sites
for GHF-1. Thus, many different factors regulate the
expression of the GH gene. A review of all factors
thataffectGHgeneexpressioncanbefoundinTheill
JAK-STAT
and Karin (1993).
254 Scott Chappel and William Murphy
Important homologies lymphoma(Wu et al., 1996),as well as lymphoidand
myelomonocytic cell lines (Palmetshofer et al., 1995).
As an immune modulator, GH may be delivered
Hematopoietic growth factors play important roles
either from the pituitary or it may be synthesized
in immune cell development and function (Hooghe
andsecretedlocallybylymphoidtissue.Thissuggests
et al., 1993). The receptors and their ligands in this
that the immunoregulatory action of GH may be
family include GM-CSF, G-CSF, erythropoietin,
the result of endocrine, paracrine, and/or autocrine
IL-2, IL-3, IL-4, IL-6, IL-11, and IL-13 (Wells and
communication.
de Vos, 1993). The binding surfaces of hGH and its
receptor and that of IL-4 and its receptor show
complementary structures and electrostatic potentials
RECEPTOR UTILIZATION
(Demchuketal.,1994).Inallcases,theligandinduces
cross-linking of the receptor, which induces the
activation of intracellular signaling pathways, includ- GH receptors (GHR) have been shown to be
ing the JAK/STAT system (Carter-Su et al., 1996). expressed on a variety of cell types including immune
cells. GHR have been described on human B cells
(Badolaroetal.,1994),thymiccells(deMello-Coelho
et al., 1998), and activated human tonsilar T cells
CELLULAR SOURCES AND (Thellin (1998). In addition, murine GHR have been
found to be expressed on all hematopoietic lineages
TISSUE EXPRESSION
and multiple lymphocyte subsets in all major organs
oftheimmunesystemtovaryingdegrees(Gagnerault
Cellular sources that produce
et al., 1996). Upon binding GH, the receptor di-
merizes and signals through JAK2 kinase (Harding
Extrahepatic Location of GH Receptors
et al., 1996). However, the expression of GH recep-
Lymphoid tissue of chickens, mice, rats, cattle and torsduringimmunecelldevelopmentandparticularly
humans has been shown to express high-affinity during disease and periods of stress have not been
receptors for GH (Kiess and Butenandt, 1985; Hull elucidated.
etal.,1996;Clark,1997;Chenetal.,1998;Dardenne,
et al., 1998; de Mello-Coelho et al., 1998) and IGF-1
(Clark,1997).TheGHreceptorgeneisalsoexpressed
IN VITRO ACTIVITIES
in T cells, B cells, and monocytes from humans and
rats (Badolaro et al., 1994; Rapaport et al., 1995). In vitro findings
Not only is the GH receptor present in lymphoid
tissue, but its expression is increased following acti-
The Thymus
vation of murine or bovine lymphoid cells by lectins
or anti-CD3 antibodies (Gagnerault et al., 1996; The thymus is a unique microenvironment that plays
Postel-Vinay et al., 1997; Dardenne et al., 1998). a major role in T cell lymphopoiesis. Through both
Receptors for GH and IGF-1 are also located on cellular and humoral interactions, the thymus shapes
thymic epithelial cells (Ban et al., 1991). theTcellrepertoire.GHandIGF-1,expressedlocally
or delivered from the systemic circulation, can exert
an effect upon this function. This may be through an
effect upon the T cells that migrate through the
Extrapituitary Expression of GH
thymus or on the thymus itself (Figure 3).
In addition to being responsive to GH, cells of the T cell precursors are produced in the bone marrow
rodent and human immune system (peripheral and migrate to the thymus where a small percentage
lymphocytes, thymus, and spleen) have been shown is allowed to develop. They are exported from the
toproducetheprotein.GHappearstoserveasalocal thymus to the periphery to perform their functions.
signalingmolecule(Weigentetal.,1988;Baxteretal., Developing T cells are both positively and negatively
1991; Hattori et al., 1994; Varma et al., 1993, selected based on their ability to recognize peptides
Maggiano et al., 1994; Wu et al., 1996; de Mello- bound to self major histocompatibility complex
Coelho et al., 1998). Differences in the amount of (MHC)proteins. Themajorityofdeveloping cells are
expressionofGHhavebeenobservedinimmunecells destroyed in the thymus. Thus, the thymus plays an
of different states of activation (Weigent et al., 1988; important role in the constant production and selec-
Hattori et al., 1994). GH expression has also been tionofnaı¨veTcellstodefendthebodyagainstinvad-
detected in a thymoma, a T cell lymphoma, B cell ing pathogens. As the individual ages, the thymus
Growth Hormone 255
Figure 3 The role of growth hormone, IGF-1, and somatostatin on immune development. GH and IGF-1
have been demonstrated to promote hematopoiesis, particularly the megakaryocyte and erythroid lineages,
both in vitroand in vivo. Somatostatin hasbeen demonstrated to inhibithematopoietic growth factor release
bylymphocytesandthereforemayexertinhibitoryeffectsonhematopoiesisinvivo.GHandIGF-1havealso
been demonstrated to promote early B cell development which occurs in the bone marrow (BM). There is
evidence that NK cell development, also believed to occur in the BM, is upregulated by GH. Both GH and
IGF-1 have been found to promote the survival of T cell progenitors. Both GH and IGF-1 have been
demonstrated to promote T cell development in the thymus, although the precise stage(s) have yet to be
delineated. GH and IGF-1 have been found to promote T cell chemotaxis and therefore may play a role in
normallymphocytecirculationtothelymphnodesandspleen.Attheselymphoidorgansanimmuneresponse
canoccurandbothGHandIGF-1canpromote,whereassomatostatinmayinhibit,antigen-specificimmune
function.
†
+? IGF-1
T +
GH + ?
pre-T pre-T
Thymus T
Lymph node
G+H + T Mf
IGF-1 pro-T GH B
+
+? IGF-1
+
? –
Bone PSC ? NK
IGF-1
marrow Somatostatin
GH +
MSC LSC + GH + GH
IGF-1 ? –
RBC pre-B +
+ +
PMN sigM– pre-B Spleen
GH PLT Monocyte sigMto Mf
+ B
IGF-1 + –? B220++ sigMn B T
Somatostatin
involutes. Circulating levels of GH show a similar 1991;Murphyetal.,1992d;Berczi,1994;Savinoetal.,
age-related decline. As described below, administra- 1995; Montecino-Rodriguez et al., 1998), as well as
tion of GH to aged individuals improves thymic the function and proliferation of thymic epithelial
function. This decrease in thymic function reduces its cells (TEC) (Timsit et al., 1992). Thymulin, a hor-
ability to support optimal T cell development. The mone produced by the thymus that plays a role in
number of naı¨ve T cells declines, with a resultant the development and maintenance of immune func-
increase in the relative number of memory T cells in tion, is synthesized and secreted in greater amounts
the periphery. Suboptimal function of the aged under the influence of GH and IGF-1 (Goff et al.,
immune system is due, in part, to thymic involution 1987;Timsitetal.,1992).Thymulinandotherthymic
and may be due at least in part by reductions in peptides have differentiating properties on T cell
pituitary GH release. maturation (Robert and Geenen, 1992). GH stimu-
lates DNA synthetic activity of thymic lymphocytes
directly or indirectly through its effects upon the
Effects of GH on Thymic Cells
function of thymic epithelial cells (Sabharwal and
Both GH and IGF-1 stimulate thymic growth, Varma, 1996; Fukushima et al., 1997; Lin et al.,
cellularity, and function (Berczi et al., 1991; Gala, 1997).
256 Scott Chappel and William Murphy
Effects of GH on Thymocytes and Thymic Function proliferationinratsandmonkeys(Berzi,1994;Kelley
etal.,1996;Kooijmanetal.,1992;Binderetal.,1994;
Thymocytes have been shown to synthesize both GH
LeRoith et al., 1996; Geffner, 1997). Growth hor-
and IGF-1 (Sabharwal and Varma, 1996). A dose-
mone has been shown to increase the activity of
related increase in thymocyte proliferation has been
cytotoxic T cells in mixed lymphocyte cultures (Snow
demonstrated in cultures of cells by the addition of
et al., 1981; Benfield et al., 1994) (Figure 4).
GH or IGF-1 (Gala, 1991; Weigent, 1996; Murphy
GH promotes the differentiation of T helper cell
et al., 1995; Kelley et al., 1996). GH stimulates the
subsets from uncommitted TH0 cells and stimulates
transcription of cytokines within fetal thymocytes,
TH1-type immune responses (Gonzalo et al., 1996).
specifically, IL-1, IL-6, and GM-CSF (Chen et al.,
When administered at the time of immunization, GH
1998). These cytokines are involved in thymocyte
induces a TH1 cytokine response to HIV-1 envelope
development and proliferation. The expression of
proteingp120comparedwithcontrols(Melladoetal.,
extracellular matrix ligands and their receptors, to
1998). Administration of human GH increases T cell
allowforincreasesinTcelltrafficking,isincreasedby
progenitor development in mice that are deficient in
GH exposure. This improves thymocyte adhesion to
endogenous GH (Murphy et al., 1993).
thymic epithelial cells which play a key role in
intrathymic T cell differentiation (Taub et al., 1994;
de Mello-Coelho et al., 1997).2 Local Expression of GH and IGF-1 by T cells
T cells have the transcription factors necessary to
Effects of GH on Peripheral T Cells
express the mRNA for GH and produce biologically
Binding of GH to its high-affinity receptor expressed activeGHandIGF-1inculture(Weigentetal.,1988;
onTcellsexertsanumberofresponses.Theseinclude Geffneretal.,1990;Baxteretal.,1991;Delhaseetal.,
the expression of IGF-1, an increase in T cell prolif- 1993; Hooghe et al., 1993; Varma et al, 1993; Hattori
eration and augmented lectin- and anti-CD3-induced et al., 1994; Auernhammer and Strasburger, 1995;
Figure4 RoleofGH,IGF-1,andsomatostatinonimmunefunction.
Antigen (Ag) is phagocytosed by antigen-presenting cells (APCs) and
proteolytically porcessed. It is then bound with class II MHC
moleculesonthecellsurface.GHandIGF-1havebeendemonstrated
to augment macrophage function and therefore may affect Ag
processing. Somatostatin has been shown to inhibit inflammatory
responses. Both GH and IGF-1 have been found to promote T cell
proliferation and function (i.e. cytokine production or cytotoxicity).
Somatostatin may inhibit these activities. GH and IGF-1 have also
been shown to induce B cell proliferation and immunoglobulin (Ig)
production and act as switch factors for particular isotypes.
CD8+
cytotoxic
GH
T-cell
+ +
Somatostatin
GH IGF-1 – ?
Ag ? + +
+ IGF-1
Ag Proliferation
Somatostatin processing + +
– – CD4+ IGF-1
T-helper
Inflammatory TCR cell
cascade
APC
Cytokines Class II Ag
presentation
GH
B
+
cell
+ IGF-1
GH IGF-1 + Ig
+ Proliferation
IGF-1 +
Isotype
switching
Ig production
Growth Hormone 257
Sabharwal and Varma, 1996; Wu et al., 1996). 1992). In this report, GH-primed alveolar macro-
Leukocytes, activated by a nonspecific mitogen such phages both in vitro and in vivo. GH has been shown
as PHA, secrete greater amounts of GH and IGF-1 to improve immune function in burned mice by
than unstimulated cells (Weigent et al., 1988; increasing the production of cytostatic macrophages
Gagnerault et al., 1996). (Takagi et al., 1997). GH can protect the host from
ExperimentalreductionsinGHreleaseorsignaling a lethal bacterial infection by promoting the matu-
affect T cell proliferation. Administration of GH ration and function of macrophages and other
antisera prevents the proliferation of lymphocytes in phagocytes (Saito et al., 1996). Both GH and IGF-1
culture (Pierpaoli and Sorkin, 1968; Weigent et al., are potent signals for priming human and porcine
1988).DecreasesinGHsignalingcanalsobeachieved PMNs to secrete superoxide anions (O ) (Fu et al.,
2
by preventing the transcription or translation of the 1991;Wiedermannetal.,1993a).Itappearsthatthese
GH gene. Antisense oligonucleotides against GH molecules act in a paracrine fashion to prime PMNs
mRNA, when incubated with lymphocytes, reduces for enhanced respiratory bursts. GH is expressed in
their rate of proliferation (Weigent et al., 1991). humanneutrophils(Balteskardetal.,1997;Kooijman
et al., 1997b; Melen et al., 1997). GH may act to
Effects of GH and IGF-1 on NK Cell Function increase host resistance to disease by increasing the
release of toxic oxygen metabolites by the innate
IGF-1 and GHbind with high affinity and specificity
immune system to combat infections.
toNKcells.Bothofthesehormoneshavebeenshown
to stimulate CD16+ natural killer cell activity
GH and Cytokines
(Bidlingmaier et al., 1997). Natural killer cell activity
is depressed in aged rats and administration of GH The effects of GH on lymphoid cell activity,
can restore function (Davila et al., 1987). A decrease engraftment, and migration may be the result of
in NK cell function has been demonstrated in GH- stimulationofcytokinesknowntocontributetothese
deficient patients (Crist et al., 1987; Bozzola et al., activities. GH stimulates the expression of IL-2
1990). Administration of recombinant GH corrected (Schimpff and Repellin, 1990) and several cytokines
the decrease in NK activity in GH-deficient children by thymic epithelial cells (Tseng et al., 1997; Chen
(Berczi, 1994). et al., 1998). Likewise, IGF-1 potentiates the pro-
ductionofIL-2fromhumanTcellsandenhancesthe
Effects of GH and IGF-1 on B Cells rate of differentiation of progenitor cells to mature
lymphocytes (Clark, 1997). While there may be a
GH stimulates thymidine incorporation into human
direct effect of GH and IGF-1 on immune cell
plasma cell lines and can increase the production of
function, itmayalsobe stimulatedindirectlythrough
immunoglobulins (Igs) in these cells (Yoshida et al.,
an effect on cytokine expression in the responsive
1992, Kimata and Yoshida, 1994; Kimata and
tissue.
Fujimoto, 1994). In addition, GH has been shown
toenhancetheproductionofmanydifferentclassesof
Igs including IgGs, IgAs, and IgMs (Kimata and GH and Hematopoiesis
Fujimoto,1994).Theseeffectsareblockedbycoincu-
GH administration promotes the proliferation of
bation of B cells with antibodies against human GH.
hematopoietic cells, particularly bone marrow-
GH and IGF-1 have been shown to induce IgE and
derived progenitor cells. In combination with GM-
IgG class switching (Geffner, 1997; Rapaport and
CSF, GH doubled the number of precursor cells that
Bozzola, 1997). GH administration increased splenic
differentiated into granulocytes and stimulated
follicles and splenic B cell populations in aged
granulopoiesis in vitro (Merchav et al., 1988) as well
monkeys(LeRoith et al., 1996). In contrast, transient
as a variety of other hematopoietic lineages in vivo
decreases in B cell numbers have been reported in
(Murphy et al., 1992c). GH and IGF-1 have been
children during GH administration (Wit et al., 1993;
shown to inhibit apoptosis in hematopoietic progeni-
Rapaport and Bozzola, 1997).
tors (Minshall et al., 1998) and stimulate the produc-
tion of murine and human red blood cells in vitro
Effects of GH and IGF-1 on Monocytes,
(Golde et al., 1976; Christ et al., 1997). In numerous
Macrophages, and Polymorphonuclear Cells
animal species, as well as humans, administration of
Monocyte chemotaxis is stimulated in vitro by the GH causes an increase in hemoglobin levels (Ten
administration of GH (Wiedermann et al., 1993b). Have et al., 1997).
GH has also been shown to induce superoxide anion As summarized above, GH exhibits effects upon
production in macrophages (Edwards et al., 1988, a variety of cell types within the immune system.
258 Scott Chappel and William Murphy
In addition to enhancing the inherent activities of atrophy of the thymus and spleen. Dwarf mice have
the cells, GH also acts with other factors to stimulate deficits in CD4+ CD8+ double positive thymic
hematopoiesis and immune cell development and cells. These deficiencies are partially reversed by
function. administration of GH (Baroni et al., 1969; Murphy
et al., 1992b, 1992d; Schurmann et al., 1995).
Administration of GH to dwarf mice resulted in a
significant increase in thymocyte proliferation
IN VIVO BIOLOGICAL
(Murphy et al., 1993).
ACTIVITIES OF LIGANDS IN
Immune function can also be partially restored by
ANIMAL MODELS administration of GH-producing lymphocytes into
these dwarf animals (Weigent and Blalock, 1994).
Normal physiological roles These experiments support the contention that pitu-
itary GH plays a significant role in immune function.
Hypophysectomy and Other Methods to
Reduce GH Signaling
Transgenic overexpression
Since 1930, it has been known that hypophysectomy
(removal of the pituitary gland) suppresses both
As further evidence for a role for GH as a stimulator
hematopoiesis and immune cell proliferation (Smith,
of hematopoiesis, mice transgenic for either bovine
1930).Italsoinducesastateofimmunodeficiencyand
GH or human GH-releasing hormone (hGHRH)
thymichypoplasiainrodents(Nagyetal.,1987;Gala,
exhibited splenic hyperplasia with increased num-
1991). Administration of antiserum to GH also
bers of erythroid and megakaryocytic progenitors.
induces thymic atrophy and smaller spleens in mice
Further, splenocytes from these transgenic animals
andrats(Fabrisetal.,1971;Berczietal.,1983).These
had a higher proliferative index than controls when
defectsinimmunefunctioninrodentscanbereversed
infusedintoirradiatednontransgeniccontrols(Blazar
by the administration of GH (Berczi et al., 1983).
et al., 1995).
Hypophysectomized rats have additional evidence
Mice treated with azidothymidine (AZT) to induce
for impaired immune function such as reduced rates
myelotoxicity, show a significant increase in splenic
of survival after bacterial infections (Edwards et al.,
and bone marrow progenitor cell content and hema-
1992), contact sensitivity to allergens (Berczi et al.,
tocritaftertheadministration ofrecombinanthuman
1983), and reduced ability to produce antibodies and
or ovine GH. Bone marrow cellularity, hematocrit
rejectskinallografts(Fabrisetal.,1971).GHmayact
values, white blood cell count, and splenic hemato-
to protect the host by stimulating leukocyte matura-
poietic progenitor cell counts were all significantly
tion and migration, production of cytokines and
increased in this model after GH administration
other chemoprotectants (Saito et al., 1996).
(Murphy et al., 1992c). A similar effect is observed
Injections of both GH and its primary IGF-1
after treatment of this mouse model with IGF-1
increase the weight of lymphoid organs and induce
(Tsarfaty et al., 1994; Montecino-Rodriguez et al.,
the proliferation and activity of cells within many
1998). GH has been shown to increase thymic
different components of the immune system
recovery in rats after cyclosporin administration
(Auernhammer and Strasburger, 1995, LeRoith
(Beschorner et al., 1991). Recombinant human GH
et al., 1996).
also stimulates the engraftment of human or murine
Tcellsintoseverecombinedimmunodeficient(SCID)
mice (Murphy et al., 1992a).
Knockout mouse phenotypes
Pharmacological effects
Growth hormone-deficient mice (Snell-Bagg and
Ames) have been used in many studies to determine
the effect of GH on immune function. These mice These reports show that GH has a wide variety of
lack somatotropes (GH-secreting cells) and other effects upon the immune system in animals models
cell types (lactotropes and thyrotropes) within the and in vitro. GH administration has an effect upon
anterior pituitary gland. The molecular basis for the thymic function, T cell proliferation and colonization
dwarfism is the absence of a nuclear transcription withinthethymus,migration,andengraftment(Taub
factor, pit-1, that is required for GH gene transcrip- et al., 1994; Mackall and Gress, 1997; Montecino-
tion (Li et al., 1990). Pit-1-deficient dwarf mice have Rodriguez et al., 1998). Thus, these reports suggest
impaired cell-mediated immune responses and that GH administration may enhance hematopoietic
Growth Hormone 259
and lymphoid reconstitution after myeloablation or (Kundigetal.,1993).Thereisagrowingconsensusin
bone marrow transplantation (Tian et al., 1998). the scientific community that signaling paths critical
to the survival of the species are necessarily redun-
dant. Thus, the absence of a distinct immunological
PATHOPHYSIOLOGICAL ROLES phenotype in GH-deficient people could reflect com-
IN NORMAL HUMANS AND plementary effects from other cytokines or hormones
with which GH shares this responsibility.
DISEASE STATES AND
Given the minimal effects of hypopituitarism or
DIAGNOSTIC UTILITY GH deficiency on immune function in humans and
the supposition that GH acts in concert with other
Role in experiments of nature and immune modulators to assure normal function, why
disease states should reductions in systemic GH by hypophysect-
omy or administration of GH antiserum to rats or
Immunological Status of Individuals mice affect immune function? Clark (1997) has pro-
with GH Deficiency posed an interesting explanation based upon a com-
parison of circulating levels of GH in the rat and
There are virtually no immunological abnormalities
human. Human GH levels are generally lower than
reported in growth hormone-deficient patients and
those in rats. Further, rat immune cells generally
data with GH administration is inconclusive. GH
produceloweramountsofGHcomparedwithhuman
administration does not affect (enhance) immune
cells. The rat and mouse may have a greater
functioninthesepatients(AbbassiandBallanti,1985;
dependence upon systemic GH for immune function
Rapaport et al, 1986, 1987; Petersen et al., 1990;
compared with the human. Thus, removal of the
Spadoni et al., 1991; Wit et al., 1993, Kappel et al.,
pituitary-derived component of GH may have a far
1993; Carroll et al., 1998). Several studies have
greater impact on immune function in the rodent.
suggestedthatadultsandchildrenwithGHdeficiency
have impaired NK cell killing activity (Abbassi and
Bellanti,1985;Cristetal.,1987;Bozzolaetal.,1990). Aged and Critically Ill Patients
NK function can be partially restored by GH
A common feature in age-related alterations of the
administration. Conversely, a transient reduction in
immune system is thymic involution. Thymic involu-
circulating B cell numbers has also been reported in
tion is not an irreversible process. Regrowth of the
childrenafterGHtreatment(Witet al.,1993).Lower
thymus and improvement in thymic function have
plasmalevelsofthymulinwerenotedinGH-deficient
been observed after GH administration to mice
children compared with age-matched healthy chil-
(Murphy et al., 1992d; Montecino-Rodriguez et al.,
dren.AdministrationofGHtoGH-deficientchildren
1998), rats (Kelley et al., 1986; Goya et al., 1993;
resulted in an increase in plasma levels of thymulin
Kelley, 1995), dogs (Goff et al., 1987), monkey
(Mocchegiani et al., 1990).
(LeRoith et al., 1996), and humans (Davila et al.,
Most immune parameters are normal in GH-
1987;Mocchegianietal.,1990).Age-relateddecreases
deficient patients. Paracrine- and autocrine-produced
in thymic function are reversed by the administration
GH levels are not affected by a dysfunction in
of growth hormone-secreting pituitary tumor cells
pituitary GH synthesis and release. Further, a num-
(Kelley et al., 1986). Further, treatment of aged men
ber of cytokines and growth factors are still available
and women with GH-releasing hormone elicited
to stimulate immune function in these individuals.
significant increases in B cell number and responsive-
In light of the experimental evidence in rodents
ness, IL-2 receptor expression on T cells (Khorram
reviewed above, how can GH deficiency in humans
et al., 1997a, 1997b).
resultinsuchamodesteffectuponimmunefunction?
Thymic involution occurs with aging, which is
As shown above, there is a wealth of evidence to
presumed to affect immune function (Montecino-
document the presence of GH and its receptor
Rodriguez et al., 1998). However, the exact contribu-
throughouttheimmunesystem.Nearlyallagentsthat
tion of this phenomenon to immune activity has not
influence immune or hematopoietic function are
been systematically assessed in older patients. Elderly
redundant in their action with one or more other
persons have increases in the rates of cancer,
peptides, hormones, or cytokines. It should be
infection, and fatality from pneumonia compared
recalled that IL-2 has long been considered to be a
with younger persons (Gelato, 1996). Elderly indivi-
cytokinecentraltoTcellfunction.Interestingly,mice
duals also have dramatically reduced GH levels and
lacking the IL-2 gene show normal primary and
immune function. Other benefits of GH administra-
secondary T cell responses as well as B cell activity
tion to elderly and critically ill patients are well
260 Scott Chappel and William Murphy
recognized. These include increases in nutrient utili- et al., 1992). Due to its documented effects upon
zation, reduction of body fat, normalization of sen- hematopoiesis, thymic function, and immune cell
sitivity to insulin, and increases in lean tissue mass activity, the use of GH for immune reconstitution
(Vancer, 1990; Ziegler and Leader, 1994; Hwu et al., certainly warrants indepth consideration (Hirschfeld,
1997; Johannsson et al., 1997; Carroll et al., 1998). 1996; Geffner, 1997).
Thymic regrowth, induced by GH administration
would be expected to stimulate many aspects of the Immunocompromised Patients after Bone Marrow
lymphoidsystem.GH’stherapeuticutilityinavariety Transplantation or Radiation or Chemotherapy
of NK-sensitiveinfections and neoplasiasshould also
Due to age-related thymic involution, bone marrow
be considered. The augmented killing ability of NK
transplantation results in a sustained period of
cells (Crist et al., 1987), neutrophils (Fu et al., 1991;
immunodeficiency. GH and IGF-1 therapy has been
Balteskard et al., 1997), and macrophages (Edwards
shown to be of benefit in bone marrow transplan-
et al., 1988, 1992) treated with GH suggests that GH
tation due to its ability to stimulate the thymus
therapy may be beneficial to patients at risk of
(Montecino-Rodriguez et al., 1998), to induce lym-
infection.Thesewouldincludetheelderlyorimmuno-
phocyte proliferation, and to increase splenic and
compromised persons (transplant recipients, HIV-
bone marrow hematopoietic progenitor cell content
infected, myelosuppressed, myeloablated, etc.).
and cellularity (Murphy et al., 1992c; Tian et al.,
Due to GH’s ability to stimulate lymphopoiesis
1998). Following engraftment, administration of GH
aswell asitsstimulatoryeffectsuponthethymus,the
may be expected to increase the rate of immune
utility of this pleiotropic hormone as an immune
reconstitution and decrease the duration of exposure
stimulant in the aged population should be critically
to opportunistic infections post transplantation.
evaluated.
However, as GH and IGF-1 have been shown to
promote the growth of some tumors in vitro,
HIV-infected Individuals additional studies will be required before one could
consider clinical use of GH in instances of neoplasia.
Although the newly developedinhibitorsofproteases
are effective in reducing the proliferation of the
human immunodeficiency virus (HIV), rejuvenation
of the immune system of infected individuals remains
IN THERAPY
a new challenge. GH is now being used to improve
the lean body mass of HIV-infected cachectic
Clinical results
individuals (Larkin, 1998; Mulligan et al., 1998).
Recently, a pilot study suggested that GH has an
immunostimulatory effect in HIV-infected patients GH has been demonstrated to exert numerous sti-
(Nguyen et al., 1998). GH may be of therapeutic mulatory effects on immune and hematopoietic
value to promote T cell development, recirculation, parameters. GH may therefore provide a therapeutic
and activity in the HIV-infected immunocompro- benefit to individuals requiring rapid immune
mised patient. reconstitution. This would be important after
The thymus is a major target of HIV infection. chemotherapy, radiation therapy, bone marrow
Thymic infection by HIV or SIV results in an transplantation, viral infection, or in aging. The
increased rate of thymic dysfunction and pro- mechanism by which GH exerts these immunomodu-
grammed cell death (apoptosis) of thymocytes latory effects is only now being elucidated. GH and
(McCune, 1997; Wykrzykowska et al., 1998). HIV- IGF-1 may stimulate thymic function and accelerate
infected patients with thymic dysfunction have a immune reconstitution. Other effects on the bone
significantly greater mortality than those without. marrow and mature immune cell function would also
Therapies that can reverse thymic involution would be expected to play a role. Pituitary secretion of GH
therefore be expected to dramatically improve may not be of great importance in immune
immune function following therapies to treat HIV competence in humans (unlike other species).
infection (Mackall and Gress, 1997; McCune, 1997). However, its administration during an immunocom-
In addition, GH effects on neutrophils, macro- promised period may be of great therapeutic and
phages, and NK cells may have a benefit in the economic value to decrease the length of time that a
reconstructionoftheimmunesystemofHIV-infected patient is without the full protection of the immune
individuals.GHhasbeenreportedtoaffectpositively system. The precise physiological role(s) of GH on
thymocyteprogenitorsinthebonemarrowatanearly immune parameters need to be studied in much
stageoftheirdevelopmentinthethymus(Knyszynski greater detail, regardless of clinical utility.
