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Endocrinology Vol. 138, No. 9 3949-3955
Copyright © 1997 by The Endocrine Society

ARTICLES

Growth Hormone Expression in Murine Bone Marrow Cells Is Independent of the Pituitary Transcription Factor Pit-11

Ron Kooijman2, Anagha Malur, Sylvia C. van Buul-Offers and Elisabeth L. Hooghe-Peters

Department of Pharmacology, Medical School, Free University of Brussels (V.U.B.), B-1090 Brussels, Belgium; and Pediatric Endocrinology, University Hospital for Children and Youth "Het Wilhelmina Kinderziekenhuis", 3512 LK Utrecht, The Netherlands

Address all correspondence and requests for reprints to: Ron Kooijman, Department of Pharmacology, Medical School, Free University of Brussels, Laarbeeklaan 103, B-1090 Brussels, Belgium. E-mail: rkooi{at}farc.vub.ac.be


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
GH has been shown to promote the development and function of leukocytes. The expression of both GH and GH-receptors in lymphoid cells has led to the hypothesis that GH acts in an autocrine or paracrine fashion. The described effects of GH on hematopoiesis and B cell development, led us to investigate GH expression in bone marrow cells. By immunocytochemistry, we show that bone marrow-derived granulocytes and macrophages contain immunoreactive GH. We found that 65 ± 24% of the granulocytes were stained with anti-GH, whereas 5.8 ± 1.5% of the granulocytes contained detectable amounts of GH mRNA as assessed by in situ hybridization. To address a possible alternative regulation mechanism in bone marrow and to establish whether locally derived GH might still play a role in pituitary-deficient dwarf mice, we also addressed GH expression in bone marrow from hypopituitary Snell dwarf mice. These mice have a mutated gene for the pituitary transcription factor Pit-1 that is deficient in DNA binding. Our finding that GH expression (immunoreactive protein and mRNA) in bone marrow cells from dwarf mice is similar to that in normal mice points to a Pit-1 independent regulation of GH in mouse bone marrow.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
GH HAS BEEN implicated in the function and development of the immune system (1, 2). In rats, GH increases cellular and humoral immune responses (3), and it stimulates the nonspecific immune system (4, 5), whereas immunoneutralization of GH results in an impaired humoral response (6). Hypopituitary dwarf mice have been used to address the role of pituitary hormones in the development and function of the immune system. The Snell (dw) (7) and the Jackson (dw/J) dwarf mouse (8) have different mutations in the Pit-1 gene on chromosome 16 encoding the transcription factor for pituitary GH, PRL, and TSH (9).

Both mutations result in a hypoplasia of somatotrophs, lactotrophs, and thyrotrophs in the anterior pituitary (9). As a consequence dwarf mice are deficient in serum GH, PRL, and thyroid hormones (10, 11, 12). Both dwarf strains exhibit a cellular depletion in bone marrow, thymus and peripheral lymphoid tissues, and show an impaired cellular and humoral immunity. Early studies with dwarf mice showed that GH increases thymic cellularity and the number of nucleated cells in spleen and stimulates the humoral immune responses (1, 13, 14). More recent studies revealed that GH increases the number of peripheral T and B cells (15, 16) and the number of different thymocytes stages (17). Additionally, GH augments the hematopoietic progenitor cell content in bone marrow and spleen, and increases the number of peripheral white blood cells, erythrocytes and platelets (16). In normal mice, recombinant human GH (rhGH) increases the hemopoietic progenitor cell content in bone marrow and spleen (18). Furthermore, GH stimulates the engraftment of human T cells in severe combined immunodeficient mice (19).

The expression of GH in leucocytes (20, 21, 22, 23), and the in vitro effects of GH on cells of the immune system (1) have led to the hypothesis that GH acts in an autocrine or paracrine fashion (24). Indeed, antisense oligonucleotides to GH mRNA that inhibit GH synthesis by rat lymphocytes decrease lymphocyte proliferation (25) and GH from human thymocytes acts as an autocrine growth factor by stimulating local secretion of insulin-like growth factor I (IGF-I) (26).

The aim of the present work was to further address GH expression in cells of the immune system. The described effects of GH on hematopoiesis and B cell development, led us to investigate GH expression in bone marrow cells. To address a possible alternative regulation mechanism in bone marrow and to establish whether locally derived GH might still play a role in pituitary-deficient dwarf mice, we compared GH expression in bone marrow from both normal and dwarf mice. We show that a subset of bone marrow-derived granulocytes from both normal and Pit-1 deficient dwarf mice express GH. These results point to a Pit-1 independent regulation of GH in mouse bone marrow.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Reagents
Monkey antimouse GH (35–12/1/70) and rat GH (NIDDK-rGH-B-14-SIAFP; AFP-3699A) were donated by The National Hormone and Pituitary Program (NIDDK, NIH, Bethesda, MD). According to the specifications, antimouse GH antiserum does not cross react with other pituitary hormones. Peroxidase-conjugated antimonkey IgG was obtained from Sigma Chemical Co. (St. Louis, MO).

Mice
Snell dwarf mice (dw/dw) and heterozygous controls (dw/+) were weaned at 41/2 weeks of age and maintained as described before (27). All mice used were 10-week-old females. The protocol received approval of the committee for Animal Experiments of the Medical Faculty, University of Utrecht.

Cell and tissue preparations
Mice were killed by decapitation after ether anesthesia. Pituitaries were collected directly after decapitation, frozen in liquid nitrogen and stored at -80 C. Sections of 7–10 µm were cut between -20 and -25 C using a cryomicrotome.

Suspensions of bone marrow cells were prepared from femora and tibiae in HBSS supplemented with 5% FCS. The bones were cleaned of muscles and tendons, and ground in a mortar. Single cell suspensions were obtained by aspiration through a 21-gauge needle. The number of nucleated cells was determined by counting an aliquot stained with Türk’s solution in a Bürker-Turk counting chamber. Bone marrow cells were washed in PBS and centrifuged onto 3-aminopropyltriethoxysilicane coated glass slides for 5 min at 50 x g using a Cytospin.

Slides with either pituitary sections or bone marrow cells were air-dried and fixed in 4% paraformaldehyde for 10 min at room temperature and washed three times in PBS, dehydrated in graded ethanol, and stored at 4 C in 70% ethanol until use.

Immunocytochemistry
The endogenous peroxidase activity was inhibited by treatment with 6% H2O2 in 80% methanol for 15 min at room temperature. Subsequently, the slides were washed three times in PBS. Thereafter, the cells were incubated with a 1:1000 (pituitary sections) or 1:100 (bone marrow cells) dilution of monkey antimouse GH antiserum in PBS containing 20 µg/ml BSA for 18 h at 4 C. After three washings in PBS, the slides were incubated with peroxidase-labeled rabbit antimonkey IgG (1:50 dilution in PBS containing 10% normal goat serum) for 30 min at room temperature. Peroxidase was visualized with 10 mg/ml 3'3-amino-9-ethylcarbazole and 0.01% H2O2 in 50 mM acetate buffer, pH 4.9, and the nuclei were counterstained with hematoxylin. Control stainings included anti-GH antiserum in PBS containing 20 µg/ml rat GH instead of BSA.

In situ hybridization
Pituitary sections and bone marrow cells were hybridized with DNA complementary to rat GH cDNA (28) labeled by random priming with 35S as described before (29). After hybridization, the slides were washed twice in 2 x SSC/50% formamide for 30 min at 30 C, followed by two washes in 2 x SSC for 30 min at 30 C and two washes in 0.1 x SSC for 30 min at 37 C. Detection of the 35S-labeled probe was performed as described before (29). Control experiments included pretreatment of slides with RNase before prehybridization (not shown), and hybridization of bone marrow cells with an irrelevant probe, i.e. rat albumin (30).

RNA extraction, RT-PCR amplification
Total RNA was extracted from 107–108 bone marrow leukocytes by homogenization in guanidine isothiocyanate and acid phenol-chloroform extraction (31). Messenger RNA was reverse-transcribed from 3 µg total RNA using 200 U Moloney murine leukemia virus reverse transcriptase (GIBCO BRL, Gaithersburg, MD) and 1.6 µg oligo(pdT)12–18 primer (Pharmacia Biotech, Uppsala, Sweden). The reaction mixture (30 µl final volume) further contained 50 mM Tris-HCl, pH 8.3, 75 mM KCl, 3 mM MgCl2, 10 mM DTT, 13 units RNAsin (Promega, Madison, WI), and 0.5 mM of each dATP, dGTP, dTTP, and dCTP. After 1 h incubation at 37 C, the reaction was stopped by addition EDTA to 45 mM and RNA was hydrolyzed by incubation for 10 min at 65 C in the presence of NaOH (75 mM). Subsequently, the cDNA was ethanol-precipitated for 18 h at -70 C, and taken into 50 µl H2O.

The cDNA was amplified using two oligonucleotide primers corresponding to sequences within exon 2 (5'-TTA-CCT-GCC-ATG-CCC-TTG-T-3') and exon 5 (5'-AGC-TAG-GTC-TCT-GCC-TTG-T-3') of the mouse GH genes. To an 100 µl (final volume) amplification buffer (75 mM Tris-HCl, pH 9.0, 20 mM (NH4)2SO4, 0.01% Tween 20, 4 mM MgCl2, 0.2 mM of each dNTP), 200 ng of each primer, 0.5 U DNA polymerase (Goldstar: Eurogentech, Seraing, Belgium), and 3 µl of cDNA solution were added. Reaction mixtures were heated at 94 C for 2 min and subjected to 35 cycles of PCR (denaturation at 94 C for 60 sec, annealing at 52 C for 90 sec and extension at 72 C for 90 sec), followed by an incubation at 72 C for 10 min. Samples of RT-PCR products (40 µl) were precipitated, resuspended in 30 µl of the appropriate restriction buffer, and incubated with 2 U ApaI (18 h at 37 C).

Southern blotting
Restriction products, together with undigested samples, were electrophoresed in a 1.7% agarose gel, transferred by capillary transfer to a Hybond-N+ nylon membrane (Amersham), and cross-linked to the membrane by UV irradiation. The membranes were prehybridized, hybridized with peroxidase-labeled rat GH cDNA, washed, exposed to detection solution for enhanced chemical luminescence, and autoradiographed according to the manufacturer’s procedure (Amersham International plc, Buckinghamshire, UK).


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Detection of GH in bone marrow cells by immunocytochemistry
Figure 1Go shows that bone marrow cells from both Snell dwarf mice (A) and their heterozygous littermates (B) were stained with an antimouse GH antiserum. The binding of the antiserum was completely blocked by addition of rat GH (Fig. 1Go, C and D). Positive cells that could be identified after counterstaining with hematoxylin were granulocytes and macrophages. The percentage of GH stained granulocytes and the staining intensity of the positive cells were highly variable in both normal and dwarf mice. Quantitative analysis revealed that the proportions of granulocytes and macrophages containing immunoreactive GH in dwarf mice are comparable to those in control mice (Table 1Go). The expression of GH in the bone marrow from dwarf mice (Fig. 1Go) is in marked contrast with the absence of GH in the pituitary from these mice (Fig. 2Go).



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  		Figure 1. GH staining of bone marrow cells from dwarf mice (dw/dw) and normal heterozygous littermates (dw/+). GH is visualized using monkey antimouse GH followed by a peroxidase-labeled goat antimonkey IgG (A, B). No signal was observed in competition experiments with 20 µg/ml rat GH (C, D). This experiment is representative of six different experiments with different mice.

 

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  		Table 1. Percentage of GH positive granulocytes and macrophages in control and dwarf mice

 


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  		Figure 2. Analysis of GH expression in frozen sections of pituitaries from dwarf mice (dw/dw) and normal heterozygous littermates (dw/+) by immunocytochemistry (A, B) and in situ hybridization (C, D). This experiment is representative of three different experiments with different mice.

 
In situ detection of GH transcripts in bone marrow cells
In situ hybridization studies revealed that GH mRNA is expressed by bone marrow from both dwarf and control mice (Fig. 3Go, A and B), whereas the pituitary from dwarf mice was completely negative (Fig. 2CGo). The staining of bone marrow cells was confined to granulocytes (Fig. 3Go, A and B) and absent when an irrelevant, rat albumin probe was used (Fig. 3Go, C and D). The fraction granulocytes in dwarf mice that contains GH transcripts (8.8 ± 3.7%) was not significantly different from the fraction in control mice (5.8 ± 1.5%; Table 1Go). Notably, in both normal and dwarf mice, the percentage of granulocytes that express GH transcripts as assessed by in situ hybridization is significantly lower (P < 0.005) than the percentage of cells that contain immunoreactive GH (Table 1Go). Indeed, double-labeling experiments show that not all bone marrow cells that contain immunoreactive GH express detectable levels of GH transcripts (Fig. 4Go).



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  		Figure 3. Identification of GH mRNA in bone marrow cells from dwarf mice (dw/dw) and normal heterozygous littermates (dw/+). Cells were labeled by in situ hybridization with 35S-labeled rat GH cDNA (A, B). An irrelevant probe, rat albumin cDNA, was used as a control for aspecific binding (C, D). This experiment is representative of six different experiments with different mice.

 


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  		Figure 4. Double staining of bone marrow cells for GH by immunocytochemistry and in situ hybridization. After visualization of GH, cells were labeled by in situ hybridization with 35S-labeled rat GH cDNA. No signals were observed in competition experiments with 20 µg/ml rat GH or with an irrelevant probe (not shown).

 
Detection of GH transcripts by RT-PCR analysis
To confirm GH expression in bone marrow cells, we performed RT-PCR analysis on total RNA from isolated bone marrow cells. Using primers corresponding to sequences in exon 2 and exon 5, a PCR fragment of the predicted size (520 bp) was generated from cDNA and detected by Southern blot analysis using a rat cDNA probe (Fig. 5Go, lanes 1 and 3). These fragments were absent in parallel reactions lacking any cDNA template (data not shown). The specificity of the fragments was confirmed by digestion with ApaI, which cuts the predicted fragment into two 260 bp fragments (lanes 2 and 4). The results confirm that bone marrow cells from both normal and dwarf mice express GH mRNA.



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  		Figure 5. Endonuclease digestion and Southern blot analysis of RT-PCR products showing GH transcripts in the bone marrow from dwarf mice (lane 3) and normal heterozygous littermates (lane 1). Parts of the amplified products were subjected to endonuclease digestion by ApaI (lanes 2 and 4), which exactly cuts the expected 520 bp PCR product into 260 bp fragments. Restriction products, together with undigested samples were electrophoresed, transferred to nylon membranes, and hybridized with peroxidase-labeled rat GH cDNA.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
We here report for the first time that a fraction of murine bone marrow cells contain GH. Most of the granulocytes and macrophages were stained with anti-GH, whereas GH mRNA was only detected in a subset of GH containing granulocytes (Fig. 4Go). This phenomenon can be explained in several ways. Possibly, the GH containing cells store GH that is synthesized from undetectable but low levels of mRNA, or from mRNA that was expressed in an earlier stage of development. Alternatively, GH is produced by other bone marrow cells and taken up from the intercellular fluid. Because bone marrow cells were isolated in 5% FCS to prevent aggregation, we tested whether the cells took up significant amounts of bovine GH during the isolation procedure. We found that the percentage of GH containing cells was not influenced by the presence of FCS (data not shown).

In lymphocytes from bone marrow, thymus, and spleen, GH was not detected by immunocytochemistry nor by in situ hybridization (data not shown). These results imply that granulocytes express higher levels of GH than lymphocytes. This result does not imply that lymphocytes do not express GH at all because other investigators showed that lymphocytes from both rodents and humans express GH (21, 22, 26, 32, 33, 34, 35).

The presence of GH in bone marrow suggests that GH might exert autocrine or paracrine effects on hematopoiesis. This hypothesis is supported by the finding that GH receptors are expressed on leucocytes from several mouse strains (36). It was established that 22% of the bone marrow leucocytes and 50% of the peripheral B cells from C57BL mice expressed GH receptors. Furthermore, treatment of DW/J dwarf mice with rhGH augmented the hematopoietic progenitor cell content in bone marrow and spleen and increased the number of peripheral white blood cells, erythrocytes, platelets, and lymphocytes (16). GH treatment of DW/J dwarf mice increased the number of B cells in spleen, although the deficiency of B cell progenitors was not restored (16). In addition, we found that also GH increased the number of splenic B cells in Snell dwarf mice (unpublished data). In normal mice, rhGH stimulated the hemopoietic progenitor cell content in bone marrow and spleen (18).

These findings and our result that rhGH treatment of Snell dwarf mice increases the number of nucleated bone marrow cells by 86% (P < 0.005; data not shown) strongly suggest that human GH exerts hematopoietic effects in mice. It should be noted that primate GH also binds to PRL receptors and that PRL receptors are expressed in murine bone marrow cells (37, 38). A few studies were performed with bovine or ovine GH which, like murine GH, do not bind to the PRL receptor. Treatment of dwarf mice with bovine GH induced cellular repopulation of bone marrow (39), and administration of ovine GH increased the number of thymocytes (15) and splenic B cells (40). However, further experiments with nonprimate GH should be performed to establish the in vivo effects of murine GH on hematopoiesis and immune function in mice.

Because GH stimulates the expression of IGF-I in many tissues, it is possible that paracrine GH induces local secretion of IGF-I that is expressed by murine macrophages (41, 42) and stromal cells (43). IGF-I has been implicated in both B cell development (44, 45, 46) and antibody synthesis (47). However, most in vitro effects of GH on leukocytes are not mediated by IGF-I (1).

Although further investigations are necessary to establish whether GH expression in bone marrow or in peripheral granulocytes is a general feature in mammals, there are several indications that this is the case. For instance, GH is expressed in neonatal and adult rat bone marrow (22, 35, 48, 49) and a subpopulation of peripheral blood human neutrophils contains high levels of immunoreactive GH (Kooijman, R., D. Berus, A. Malur, M. Delhase, and E. L. Hooghe-Peters, manuscript submitted). Possible functions for bone marrow-derived GH in hematopoiesis and immune function in humans are indicated by several in vitro studies. It was shown that rhGH stimulates in vitro B cell proliferation, antibody synthesis (50, 51, 52) and class switch (53). Indeed, like in mice, the expression of GH receptors on human leucocytes is mainly confined to B cells (54). In addition, rhGH stimulates erythropoiesis and granulopoiesis via paracrine IGF-I (55, 56).

The pituitary homeodomain transcription factor Pit-1 plays a critical role in the trans-activation of the GH gene in the pituitary (57). Although the mutated Pit-1 in Snell dwarf mice is deficient in DNA binding (9, 58), GH expression in bone marrow cells of Snell dwarf mice is not affected as assessed by in situ hybridization, immunocytochemistry, and RT-PCR analysis. Therefore, we conclude that GH expression in murine bone marrow cells does not depend on Pit-1. Whether this implies that GH in bone marrow is regulated by other hormones or cytokines than in the pituitary remains to be established. The idea that Pit-1 is not involved in GH expression in the murine immune system is also supported by the finding of Weigent et al. (32), who showed that GH expression in subpopulations of cultured thymic and splenic lymphocytes from DW/J dwarf mice is normal. Yet, Delhase et al. (22) showed that a subset of rat bone marrow cells and splenocytes express Pit-1 transcripts. An equal fraction of bone marrow cells and splenocytes expressed GH mRNA. Furthermore, both the Pit-1- and the GH-expressing cells were located in the red pulp and the marginal zone of the spleen. Although we cannot exclude the possibility that part of the GH in these cells is regulated by Pit-1, our results indicate that Pit-1 is not required for GH expression in cells of the immune system. An alternative function of Pit-1 might be the regulation of cell proliferation (58).


   Acknowledgments
 
The authors wish to thank Mrs. M. G. Reijnen-Gresnigt, Mrs. I. van de Brink, and Mrs. J. van Benthem (Department of Endocrinology) for their technical assistance. The gift of antibodies by The National Hormone and Pituitary Program (NIDDK, NIH, Bethesda, MD) is greatly acknowledged.


   Footnotes
 
1 This research has been funded by the Fund for Scientific Research-Flanders, Belgium (F.W.O), European Communities (SC1–0252-C (TT) and institutional grants from the V.U.B. Back

2 Research associate of the Fund for Scientific Research-Flanders, Belgium (F.W.O). Back

Received April 14, 1997.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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