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(The FASEB Journal. 2000;14:1126-1131.)
© 2000 FASEB

Co-localization of TFF3 peptide and oxytocin in the human hypothalamus

WOLFGANG JAGLA*, ANTJE WIEDE*, KNUT DIETZMANN{dagger}, KAREN RUTKOWSKI* and WERNER HOFFMANN*1

* Institut für Molekularbiologie und Medizinische Chemie, Otto-von-Guericke-Universität, D-39120 Magdeburg, Germany; and
{dagger} Institut für Neuropathologie, Otto-von-Guericke-Universität, D-39120 Magdeburg, Germany

1Correspondence: Institut für Molekularbiologie und Medizinische Chemie, Universitätsklinikum, Leipziger Str. 44, D-39120 Magdeburg, Germany. E-mail: Werner.Hoffmann{at}Medizin.Uni-Magdeburg.de


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
TFF-peptides (formerly P domain peptides, trefoil factors) are typical secretory products of many mucous epithelial cells. TFF3 is also synthesized in the hypothalamus and has anxiolytic or anxiogenic activities when injected into the rat amygdala. Here we show by immunohistochemistry that TFF3 is localized to a distinct population of neurons of the human hypothalamic paraventricular and supraoptic nuclei. Generally, TFF3-positive cells are co-localized in oxytocin-producing cells and not in vasopressin-producing cells. Relatively large amounts of TFF3—but not TFF1 and TFF2—are present in the posterior lobe of the human pituitary, where it is probably released into the bloodstream. Furthermore, TFF3 was also detectable in human postmortem cerebrospinal fluid.—Jagla, W., Wiede, A., Dietzmann, K., Rutkowski, K., Hoffmann, W. Co-localization of TFF3 peptide and oxytocin in the human hypothalamus.


Key Words: pituitary • TFF-domain • neuropeptide • oxytocin • vasopressin • epithelial cell migration • anxiolytic


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
THREE TFF PEPTIDES (formerly P-domain peptides, trefoil factors; ref 1 ) have been characterized in mammals, including human beings: TFF1 (formerly pS2), TFF2 (formerly hSP), and TFF3 (formerly hP1.B/hITF). They are major secretory products of many mucin-producing cells (1 2 3 4 5) and are also found in the brain.

The physiological functions of TFF-peptides are multiple. They promote migration of epithelial cells in vitro and enhance mucosal healing and epithelial restitution in vivo in the gastrointestinal mucosa (6 , 7) . They probably also interact with mucins, influencing the rheological properties of viscoelastic mucous gels (7 , 8) . The role of TFF-peptides in the central nervous system (CNS) is probably manifold. They could influence the development of the CNS (9) or act as typical neurotransmitters/neuromodulators or hormones. For example, injections of synthetic TFF3 into the rat amygdala revealed an anxiolytic effect at a low dose and an anxiogenic effect at a higher dose (10) . However, thus far no neural abnormalities have been reported for transgenic mice lacking TFF1 or TFF3, respectively (11 , 12) .

The expression of TFF peptides in the brain is not uniform. TFF1 is expressed in the rat hippocampus, cortex, and cerebellum (9) as well as in cultured mouse astrocytes (13) , where a regulation of expression by various cytokines has been reported (14) . No data are published concerning neural expression of TFF2. Expression of TFF3 has been reported in magnocellular neurons of the rat and human hypothalamus (15 , 16) and also in the rat amygdala (15) .

The majority of magnocellular neurons of the human hypothalamus is located in the paraventricular (PVN) and supraoptic nuclei (SON), which predominantly synthesize oxytocin (OT) or vasopressin (VP) in separate populations of cells (17 , 18) . An age-dependent size pattern of sex differences has recently been reported for VP-ergic cells but not for OT neurons (19) . Thus far, there are no data describing which of the two distinct cell populations synthesizes TFF3. Most neurons of the human PVN and SON project to the posterior lobe of the pituitary (20 21 22 23) ; here, they mainly secrete OT or VP as typical neurohormones into the bloodstream. In addition, a subpopulation of neurons probably mainly of the PVN projects to the median eminence or to other brain regions, where OT and VP act as neurotransmitters/neuromodulators (21 22 23) . Many other neuropeptides co-existing with OT and/or VP have been demonstrated in the human PVN and SON (21) . Here, we address the question if TFF3 is co-localized with OT and/or VP in neurons of the human PVN and SON.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Human postmortem tissue and cerebrospinal fluid (CSF)
Postmortem time of all individuals investigated was between 12 and 24 h. Hypothalami of four individuals (between 53 and 69 years of age) were used for immunohistochemistry. Figures 1 ,2 ,3 were obtained with the hypothalamus of a 67-year-old male individual who died from a mitral defect. Single pituitary samples from 15 individuals (between 38 and 88 years of age) were extracted for TFF-peptides. Figure 4 was made with a dissected pituitary of a 72-year-old female who died due to myocardial infarction. Clear CSF was collected from the third ventricle (‘ventricular CSF’) or after passage of the cisterna magna (‘extraventricular CSF’) of 14 individuals (between 39 and 87 years of age). Figure 5 depicts the results from CSF of a 43-year-old male who died from liver cirrhosis because of alcoholism.



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  		Figure 1. Sequential immunohistochemical localization of OT and TFF3 revealed their co-localization in specific neurons of the human hypothalamic PVN. A) Staining of the PVN with a polyclonal anti-OT antiserum and immunofluorescence with Cy3-label. B) Subsequent staining of the same parasagittal section with anti-hTFF3–1 antiserum and enzymatic detection with DAB; shown is the inverse representation of a differential interference-contrast picture. Scale bars: 75 µm. C) Camera lucida drawing of two parallel parasagittal sections medial and lateral to panels A/B. CA, anterior commissure; CM, mamillary body; F, fornix; FM, foramen Monroi; OT, optic tract; PVN, paraventricular nucleus (dotted).



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  		Figure 2. Sequential immunohistochemical localization of OT and TFF3 revealed their co-localization in specific neurons of the human hypothalamic SON. A) Staining of the dorsolateral part of the SON with a polyclonal anti-OT antiserum and immunofluorescence with Cy3-label. B) Subsequent staining of the same parasagittal section with anti-hTFF3–1 antiserum and enzymatic detection with DAB; shown is the inverse representation of a differential interference-contrast picture. Scale bars: 75 µm. C) Camera lucida drawing of two parallel parasagittal sections medial and lateral to panels A/B. CA, anterior commissure; F, fornix, OT, optic tract; SON, supraoptic nucleus (dotted).



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  		Figure 3. Sequential immunohistochemical localization of TFF3 and VP in neurons of the human hypothalamic PVN. The micrographs were taken from the region as shown delineated in the camera lucida drawing of Fig. 1C . A) Staining of parasagittal section with anti-hTFF3–2 antiserum and immunofluorescence with fluorescein label. B) The same section subsequently stained with the monoclonal anti-VP-neurophysin antiserum and enzymatic detection with DAB showed that TFF3 and VP are localized in two different populations of neurons. Scale bars: 50 µm.



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  		Figure 4. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis (15%) and subsequent Western blot analysis of human anterior (A) and posterior (P) pituitary extracts. The following polyclonal antisera against TFF-peptides were used: anti-human TFF1, anti-hTFF2–1, or affinity-purified anti-hTFF3–2. The molecular size standard is shown on the left.



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  		Figure 5. SDS-polyacrylamide gel electrophoresis (15%) and subsequent Western blot analysis for TFF3 in human CSF. 15 µl ventricular CSF (lane b) or extraventricular CSF (lane c) were stained using affinity purified anti-hTFF3–2 antiserum. Recombinant human TFF3 was used as a positive control (lane a). The molecular size standard is shown on the left.

Antisera and Western blot analysis
The following antisera monitoring TFF peptides were used.

Anti-TFF1: A polyclonal rabbit antiserum against the carboxyl-terminal region of human TFF1 was purchased from Novocastra (Newcastle, U.K.).

Anti-TFF2: The synthetic peptide FFPNSVEDCHY (kindly provided by Dr. H. Kalbacher, Tübingen) representing the carboxyl terminus of human TFF2 (24) was coupled to keyhole limpet hemocyanin with glutaraldehyde and a rabbit immunized similarly, as described (25) . This resulted in the antiserum anti-hTFF2–1.

Anti-TFF3: The two polyclonal antisera anti-hTFF3–1 (raised in a chicken) and anti-hTFF3–2 (generated in a rabbit) against the carboxyl terminus of human TFF3 as well as the affinity purification of anti-hTFF3–2 were described previously (3) .

OT was localized using a commercial polyclonal rabbit antiserum (Boehringer Ingelheim, Bioproducts, Heidelberg, Germany) and VP was detected with the monoclonal antibody PS41 against rat VP-neurophysin (26) kindly provided by Prof. J. F. Morris (Oxford, Oxford, U.K.).

Tissue extraction of human pituitary samples under reducing conditions was as described previously (27) . Methods for subsequent Western blot analysis under reducing conditions were as reported in detail (27) using the various antisera in a 1:500 dilution. A peroxidase-conjugated goat anti-rabbit immunoglobulin G (IgG; Vector Laboratories, Inc., Burlingame, Calif.) was used as secondary antibody. Recombinant human TFF3 (kindly provided by Dr. L. Thim) was used for controls. The Mr was estimated by comparison with the MW-SDS-70L kit (Sigma, Deisenhofen, Germany).

General histology and immunohistochemistry
Pieces of human hypothalami were fixed in HEPES-buffered 4% paraformaldehyde overnight at 4°C and processed as described in detail previously (27) .

The fixed parasagittal sections were treated with 1% sodium borohydride (Sigma) in phosphate-buffered saline (PBS) for 15 min at room temperature, blocked with 1% bovine serum albumin (BSA) for 30 min at 37°C, and incubated with the primary antibody in 0.5% BSA (dilutions: anti-hTFF3–2 1:2000; polyclonal anti-OT 1:500) overnight at room temperature. The secondary antibodies, fluorescein-labeled goat anti-rabbit IgG (Boehringer Mannheim) or Cy3-labeled goat anti-rabbit IgG (Sigma Bioscience), were incubated for 2 h at 37°C. Nucleic DNA was stained with 4',6-diamidino-2-phenylindole (Sigma) and the sections were covered with fluorescent mounting medium (Dako, GmbH, Hamburg, Germany) after being washed in PBS and water. The slides were analyzed at this point before continuing with a second label. An enzyme detection system was used for the second labeling step after removal of the coverslips. The sections were incubated with anti-hTFF3–1 (dilution 1:10000) or the monoclonal antibody PS41 against VP-neurophysin (dilution 1:500) overnight at room temperature. The secondary antibodies, biotinylated goat anti-chicken IgG and goat anti-mouse IgG (Vector Laboratories, Inc.), were incubated for 2 h at 37°C. A ‘Vectastain ABC-Kit’ (Vector Laboratories, Inc.) was used for detection in combination with diaminobenzidine (DAB)/0.3% ammonium nickel sulfate as a substrate for horseradish peroxidase. The sections were covered again with fluorescent mounting medium and photomicrographs were taken on Kodak Ektachrome EPJ 320T.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Immunohistochemical localization of TFF3 and OT
The SON and the PVN were the only nuclei of the human hypothalamus where TFF3 could be detected by immunohistochemistry. The TFF3 immunoreactivity could be competitively inhibited with the synthetic peptide used for immunization but not by synthetic OT (data not illustrated). Only those neurons of the PVN and SON showed intense TFF3 immunoreactivity, which also contained OT (Figs. 1 and 2) . In contrast, VP was clearly present in another population of neurons not containing TFF3 (Fig. 3) . Thus, this is the first report classifying TFF3-secreting neurons of the human PVN and SON as typically OT-ergic.

Western blot analysis
The anterior and posterior lobes of 15 human pituitaries were dissected and extracts of each lobe were tested for TFF peptides using Western blot analysis. Figure 4 depicts the result of a representative experiment. Relatively large amounts of TFF3 could be detected only in the posterior lobe. In agreement with a previous report (16) , the Mr of TFF3 from the posterior pituitary as estimated from gel electrophoresis appeared somewhat higher than corresponding material from the duodenum probably to an unknown posttranslational modification (data not illustrated). TFF3 immunoreactivity could be competitively blocked by the synthetic peptide used for immunization, but not with the synthetic peptide representing the 15 carboxyl-terminal amino acid residues of human neurophysin-I (sc-7806P; Santa Cruz Biotechnology, Inc., Santa Cruz, Calif.). TFF1 and TFF2 were not detectable using this assay.

The CSF samples were also analyzed for TFF3 by Western blot (Fig. 5) . TFF3 was detectable only in the ventricular but not the extraventricular CSF. Using the same assay, no TFF3 could be detected in various human serum samples.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
This study clearly demonstrates that TFF3 is a typical neuropeptide of the human SON and PVN and that it is co-localized only with OT-producing cells but not with VP-ergic neurons. The number of TFF3-positive neurons seem to be smaller than the number of OT-ergic cells, and few OT-producing neurons could be detected that did not show TFF3 immunoreactivity (data not illustrated). The very specific expression pattern agrees with the accepted picture that neurons of the human PVN and SON consist mainly if two complementary subpopulations of cells secreting either OT or VP (17 , 18 , 21 , 22 , 28) . Only in the rat do a number of cells express both molecules, in particular, during lactation (29 30 31) . Commonly, the relatively large OT or VP cells of the mammalian PVN and SON are anatomically defined as the classical magnocellular hypothalamo-neurohypophysial neurosecretory system (23) . However, in the human PVN, in contrast to the rat, there is a continuous distribution from small to large OT and VP neurons, and neither type of neurons is localized in a particular subnucleus of the PVN (21 , 22 , 32) . Thus, in human PVN it is not possible to determine with certainty which neurons project to the posterior pituitary and which to other regions of the brain (21 , 22) .

The presence of relatively large amounts of TFF3 in the posterior pituitary is an indication that, like OT, the bulk of TFF3 is axonally transported into this area and eventually released into the bloodstream. All other TFF-peptides—TFF1 and TFF2—could not be detected in the human pituitary by Western blot analysis. Pulsatile secretion of TFF3 in the human posterior pituitary might occur simultaneously with that of OT and in response to the same stimuli, i.e., sexual activity, parturition, and suckling (22 , 33 , 34) . Furthermore, systematic release of TFF3 can be expected by analogy with OT, which shows a daily pattern in the plasma even in males, with a peak at night (35) . However, the question concerning the peripheral targets of TFF3 after its distribution by the bloodstream remains open. There are no molecular and cellular data available on specific TFF- receptors at present despite various indications for their existence (36 37 38 39 40 41 42 43) . For example, TFF-receptors, like receptors for epidermal growth factor, are expected to be located at the basolateral side of mucous epithelia (e.g., of the gastrointestinal or the respiratory tract) in order to promote their restitution, i.e., their rapid repair via cell migration (7) . Consequently, this process could be perfectly regulated via TFF3 originating from the posterior pituitary.

Alternatively to the release via the neurohypophysis, TFF3 might have a yet unknown action within the human pituitary, for example, via synaptoid contacts with pituicytes in the neurohypophysis (44) . An intrahypothalamic release of TFF3 also must be taken into consideration. In the rat, for example, such an intrahypothalamic release of OT is thought to be responsible for increased cell–cell contact between OT neurons and for the morphological plasticity of the hypothalamic nuclei (45) .

TFF3 synthesized by OT-ergic neurons mainly of the PVN is also an interesting candidate for being a neurotransmitter/neuromodulator in various brain regions innervated by these neurons (21 , 46) , e.g., the brain stem, spinal cord (47) , and the pontine tegmentum (48) . Among the central effects of OT are, for example, food uptake, affiliation, and maternal and reproductive behavior; in males OT is thought to be crucial for sexual arousal and ejaculation (21 , 22) . In particular, specific OT neurons of the PVN are considered to be the putative satiety neurons for eating behavior (21) . Patients with Prader-Willi syndrome, who suffer from gross obesity, reveal an ~40% decrease in the number of OT neurons in the PVN (32) . Thus, it might be worthwhile to investigate possible connections of TFF3 and body weight. Furthermore, TFF3 could be relevant to depression research due to activation of OT cells during this disorder (49) . In the rat, extrahypothalamic pathways connecting the hypothalamus and the limbic system (50 , 51) might be the reason for the fear-modulating activities of TFF3 observed after injection of TFF3 into the rat amygdala (10) .

TFF3 is also detectable in postmortem CSF with a gradient between the ventricular and the extraventricular space. However, there are no data with CSF obtained in vivo thus far. Other than unspecific leakage from postmortem material, one possible interpretation of this result would be a release of TFF3 by dendrites of neurons of the SON and PVN similar to that observed in the rat for OT and VP (52 , 53) particularly after estradiol stimulation (54) . Additional synthesis of TFF3 in perikarya outside the PVN and SON should be taken into consideration also.


   ACKNOWLEDGMENTS
 
We thank U. Meyer and G. Küchler for their excellent technical assistance, Prof. J. F. Morris (Oxford) and Dr. L. Thim (Novo Nordisk, Denmark) for providing antisera and recombinant TFF3, Dr. H. Kalbacher (Tübingen) for peptide synthesis, Prof. D. F. Swaab (Amsterdam) for helpful comments on the manuscript, and Drs. G. Laube and M. Oertel for many discussions. This work has been supported by the Bundesministerium für Bildung, Wissenschaft, Forschung und Technologie (BMBF, Neuroverbund 01 ZZ 9510/project B8 to W.H.) and the ‘Fonds der Chemischen Industrie’ (0163615 and 0500058 to W.H.).


   FOOTNOTES
 
Received for publication July 9, 1999. Revised for publication January 26, 2000.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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