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1 Department of Veterinary Physiology, Faculty of Agriculture, Tottori University, Tottori 680–0945, Japan2 Graduate School of Science and Technology, Kobe University, Kobe 657–8501, Japan
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(Received 30 September 2003;
accepted after revision 28 January 2004; first published online 17 February 2004)
Corresponding author E. Harada: Department of Veterinary Physiology, Faculty of Agriculture, Tottori University, Tottori 680–0945, Japan. Email: harada{at}muses.tottori-u.ac.jp
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Introduction |
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Recently, Harada et al. (1999b) demonstrated that the LF contained in milk is transported into the circulation from the intestinal lumen and excreted into bile, suggesting the possibility of entero-hepatic circulation of LF in neonatal pigs. Furthermore, an orally administered LF was not only absorbed into the systemic circulation in neonates (Talukder et al. 2002), but also absorbed in weaned pigs (Harada et al. 1999b) and young cattle (Talukder et al. 2003b). Talukder et al. (2003a) reported that a specific LF-receptor was detected in the intestines, including the duodenum, jejunum, ileum, and colon, and Peyer's patches in the jejunum and ileum in the adult cow. Interestingly, the density of the LF-receptor was higher in Peyer's patches than in other regions of the intestine. Thus it is speculated that the LF transport mechanism is closely related with lymphatic organs in the weaned animal. However, clear evidence for the LF transport route into the blood circulation from the intestinal lumen is still unknown.
Recently, we established the novel functions of bovine LF (bLF), such as antinociception (Hayashida et al. 2003a,b) and antistress (Takeuchi et al. 2003) effects within the central nervous system of rats. The antinociceptive effect has been also confirmed in rats fed a bLF-supplemented diet (Hayashida et al. 2003a), suggesting one possibility of the transport system of bLF from the intestinal lumen into systemic circulation in the rat.
The present study was carried out to investigate whether intestinally administered bLF is absorbed into the blood circulation via the epithelium of the intestine, and is then transferred into the lymph flow and finally up taken into the blood circulation.
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Methods |
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Bovine LF was provided from Tatua Biologics (Tatua, New Zealand). Purity of the bLF was 90% with iron saturation of 15%. Coliforms, E. coli, S. aureus, salmonella and listeria were not detected, and yeasts and moulds were less than 1/g. Other chemicals were purchased from the following sources: D-mannitol and Tris [hydroxymethyl] aminomethane from Wako Pure Chemical Co., Ltd. (Osaka, Japan). Bovine TF, BSA and Iodogen from Sigma (St. Louis, MO, USA). 125I radioisotope (carrier free), and Sephadex G-25 PD-10 column from Amersham Pharmacia Biotech (London, UK). The membrane filter was from Advantec MFS, Inc. (Tokyo, Japan), the goat antibovine LF antibody from Bethyl Laboratories, Inc. (Montgomery, TX, USA), the rabbit antibovine LF from Yagai Research Center (Yamagata, Japan), and the goat antirabbit IgG-peroxidase conjugate from EY Laboratories, Inc. (San Mateo, CA, USA).
Animals
Wistar-Imamichi strain male rats (220–280 g) were obtained from the Institute of Animal Reproduction (Ibaragi, Japan). The animals were maintained at a controlled temperature of 22 ± 2°C with a 12: 12-h light:dark cycle (light cycle, 07:00–19:00), and were given standard chow (CE-2, Nihon Clea, Tokyo, Japan). The use of these animals, as well as the procedures performed, were approved by the Animal Research Committee at Tottori University.
Lymphatic bLF transport
Surgery. Ten rats were fasted overnight, and then randomly divided into two groups, a non-collected thoracic lymph group (NC), and a collected thoracic lymph group (LC). Under sodium pentobarbital (Nembutal, 50 mg kg–1I.P.; Abbot, USA) anaesthesia, a cannula was inserted into the external jugular vein with 3 cm in depth in all rats to collect blood. The tip of the inserted cannula reached to cranial vena cava. The thoracic lymph duct was also cannulated with clear vinyl tubing (0.8 mm O.D.) according to the method of Bollman et al. (1948) in the LC rat.
Experimental protocols. The bLF solution (10%) was prepared in physiological saline (0.9% NaCl). Under pentobarbital anaesthesia, the bLF solution was infused into the duodenum by using a 26-gauge needle over 1 min at a dose of 1 g kg–1 body weight. Physiological saline was infused into the duodenum in control rats to check a cross reactivity with endogenous LF in plasma and thoracic lymph. The bLF solution or saline was the last pellet to the rats. Peripheral blood (0.6 ml) and thoracic lymph were collected into heparin coated tubes. Thoracic lymph fluid was harvested throughout the sampling period (before 1 h and hourly after the bLF infusion for 4 h). The sampling tube was changed to a new one hourly. Flow rate of thoracic duct lymph was estimated by subtracting the weight of the empty tube from the total weight of the collected tube. These samples were centrifuged at 4°C for 15 min. The supernatants were stored at –80°C until analysis. Amounts of absorbed bLF in the thoracic duct lymph were calculated from a flow rate of lymph and a concentration of bLF in lymph.
ELISA for bLF absorbed into lymph and plasma was assayed quantitatively by double-antibody enzyme-linked immunosorbent assays (ELISA) described by Harada et al. (1999a). The minimum detectable dose for bLF was 2 ng ml–1. The primary and secondary anti-bLF antibodies used in this ELISA system did not react with transferrin. Moreover, the endogeneous rat LF was not detected in the saline administered rats over 8 h (data not shown).
Radio-ligand receptor assay
Brush-border membrane vesicles (BBMVs) from the intestinal epithelium and [125I]-bLF were prepared by use of a modification of methods used in a previous report (Talukder et al. 2003a). In brief, the small and large intestines were collected from four rats immediately after killing by injection of an overdose of sodium pentobarbital. After washing the inside of the intestine with ice-cold saline, the mucosa was scraped with a glass slide and weighed. The mucosa was homogenized on ice in 20 volume of solution-A by use of a tissue homogenizer (Polytron, Kinematica GmBH, Switzerland). Solution-A (pH 7.5) consisted of 0.1 MD-mannitol, 1 mM Tris [hydroxymethyl] aminomethane, and 40 mM 2-[4-(2-hydroxyethyl)-1-piperazinyl] ethanesulphonic acid (HEPES). The homogenate was centrifuged several times, and finally, isolated membranes were circled by passing through a 27-gauge needle and the BBMV was preserved in –80°C for future use.
Iodogen (1,3,4,6-tetrachloro-3a, 6a-diphenylglycoluril) was used as a catalyst for the preparation of [125I]-bLF. Unbound [125I] was removed by a Sephadex G-25 PD-10 column equilibrated with the incubation buffer. The specific radioactivity of the product was typically about 160 000 cpm µg–1 of protein. The binding assay was performed in triplicate by incubation of [125I]-bLF with 20 µg of BBMV (1 mg ml–1) in a final volume of 100 µl incubation medium. The incubation medium (pH 7.4) contained 40 mM Tris-HEPES buffer, 0.1 MD-mannitol, 0.1 M NaCl, and 2 mM D-glucose as previously described by Talukder et al. (2003a). The concentration of ligand was varied from 0.125 to 20 µM. The incubation was carried out in a water bath at 37°C for 5 min, and the reaction was terminated by the addition of 1 ml of ice-cold saline. This solution was immediately vacuum-filtered through a pre-wetted 0.2 µM hydrophilic membrane (Advantec MFS, Inc., Japan), and rinsed three times with 1 ml of ice-cold saline. The filters were counted in an automatic gamma counter (WALLAC, 1480 Wizard, Finland) to determine the amount of [125I] associated with the BBMV. The non-specific binding of [125I]-bLF to the BBMV was determined by the addition of a 100-fold excess of free bLF to the incubation medium. A specific binding activity was obtained by subtracting the non-specific binding from the total.
Morphological investigation
Immediately after euthanasia, 7 animals were perfused with periodate-lysine paraformaldehyde fixative, at 30 min after intraduodenal administration of bLF. Two animals as an experimental control were also perfused with the same fixative, at 30 min after intraduodenal administration of solvent, physiological saline. Small pieces of the duodenum, jejunum, ileum, liver and mesenteric lymph node of the rats were extracted and immersion-fixed in the same fixative for 24 h at 4°C. The tissue blocks were snap frozen in liquid nitrogen with reference to an embedding method described by Barthel & Raymond (1990).
Four-µm thick frozen sections were prepared. Some sections were stained with haematoxylin-eosin for routine histological analysis, while others were stained immunohistochemically for detection of treated bLF in the tissue. The immunostaining was carried out according to the direct method, and was comprised of the following steps: (a) treatment with 0.5% H2O2 and absolute methanol for 30 min to remove endogenous peroxidase activity, (b) preincubation in 1% normal frog serum for 1 h at room temperature, (c) incubation with horseradish peroxidase-conjugated anti-bLF goat IgG (diluted 1: 100; Bethyl Laboratory, USA) for 20 h at 4°C, and (d) exposure to 3,3'-diaminobenzidine-HCl containing 0.03% H2O2. The controls for the immunohistochemical staining consisted of non-immunized goat serum substituted for the specific antiserum. The sections were counter-stained with haematoxylin.
Statistical analysis
All data were expressed as means ±S.E.M. One-way ANOVA and Tukey–Kramer multiple comparison test were performed for lymph flow rate and bLF levels in plasma and lymph. Friedman test (non-parametric test) was performed for amount of absorbed bLF in lymph after log-transformation. Differences with P < 0.05 were considered statistically significant.
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Results |
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To check an endogenous LF secretion, physiological saline was intraduodenally administered in three rats. We could not detect any immunoreactive substances from plasma and thoracic lymph fluid by ELISA (data not shown).
The lymph flow volume in the LC group peaked at 1 h after administration of bLF (1 g kg–1 body weight), then gradually declined up to 4 h (Fig. 1A). At the peak, the flow volume was about two times higher than that before the administration. However, the Tukey–Kramer multiple comparison test did not show significant differences between pre administration and each time points after the bLF administration.
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Amount of absorbed bLF in thoracic lymph during each hour is shown in Fig. 1B. The amount of absorbed bLF significantly increased at 2 h after the administration (Friedman test; P= 0.0422). Then, it gradually declined. This time course of amount bLF was closely related with the concentration of bLF in the lymph fluid.
bLF concentration in plasma
As shown in Fig. 2, after the administration of bLF into the duodenum, the plasma concentration of bLF in the NC group significantly increased (one-way ANOVA and Tukey–Kramer multiple comparison test; P= 0.0052 and P < 0.01, respectively), and reached a peak value (221.6 ± 67.7 ng ml–1) at 2 h. Then it quickly declined to 62.4 ± 23.5 and 36.5 ± 17.6 ng ml–1 at 3 and 4 h, respectively. In contrast, the plasma concentration of bLF in the LC group did not show visible changes during the experimental period. This clearly shows that the transport of bLF into plasma is blocked by an excretion of the thoracic duct lymph.
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The saturation curves of [125I]-bLF to the BBMV in the small and large intestines are shown in Fig. 3. The binding reaction in BBMVs from both intestinal regions was saturated at a concentration of 37 µM of [125I]-bLF, and the BBMV in the small intestine revealed about a two-fold higher affinity than that in the large intestine. Scatchard analysis confirmed higher binding sites (Bmax) with a higher affinity in BBMV from the small intestine than from the large intestine (Table 1), although the Bmax and affinity in both intestinal BBMV were markedly lower than those in the cow (Talukder et al. 2003a). To examine the specificity of binding, a competitive binding assay of [125I]-bLF to the BBMV was carried out with a 100 times higher concentration of unlabelled bLF. The bLF completely inhibited the binding of [125I]-bLF to BBMV (data not shown). These results indicate that the binding of [125I]-bLF to the rat BBMV is specific.
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The route of bLF transportation from the intestinal lumen to the peripheral circulation was investigated immunohistochemically. In some cases, the bLF reached the jejunum 30 min after intraduodenal administration. In the duodenum, the striated borders of villous columnar epithelial cells were bLF-positive in the apical villi (Fig. 4D). The lateral and basal cell membranes were also positive (Fig. 4D). At the apices of the villi, small vesicles with bLF-positive membranes were found in the epithelial cytoplasms (Fig. 4E). The lamina propria was also strongly positive in the villous apex. The positive intensity was gradually decreased toward the base of the villus (Fig. 4C). The villous columnar epithelial cells were negative in the basal portions of the villi and in the intestinal crypts.
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No bLF was detected in any mesenchymal and parechymal cells, or in the sublobular veins and arteries in the liver. In the mesenchymal lymph nodes, bLF was detected in the cytoplasm of macrophages, and also on some lymphocytes in the peripheral sinus and medullary sinus (Fig. 5A and B). No positive histological elements were detected in all tissues of any control (Fig. 4A and B).
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Discussion |
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In the present study, all blood samples were collected from cranial vena cava, because the thoracic duct lymph flows directly into the cranial vena cava. The plasma bLF concentration in the LC group, in which the lymph fluid was excreted from the thoracic duct, did not increase after the intraduodenal administration of bLF, while it rapidly increased in the NC group, in which the lymph fluid was not excreted. In addition, the bLF concentration in the thoracic duct lymph fluid increased in a time-dependent manner, which was associated with that in the plasma bLF level in the NC group, although the lymphatic bLF level was still low at 1 h after the infusion. Recently, Hayashida et al. (2004) reported that bLF has a nitric oxide-dependent hypotensive effect in rats. This hypotensive effect suggests that bLF can affect the blood stream in organs. Thus, bLF may activate the intestinal absorption of macromolecules in NC group. Further experiments are necessary to clarify this point. Anyway, these findings indicate that the bLF transported to epithelial cells from the lumen reaches the blood circulation via the lymphatic pathway, not via portal circulation. Thus, absorbed LF is not immediately metabolized in the liver, suggesting that it may be distributed to the whole body with an effective dose.
Recently, Kitagawa et al. (2003) reported a similar transporting system of bLF in a growing pig (10 weeks old). They mentioned that almost all of the absorbed bLF was transported via the lymphatics and the portal vein into the systemic circulation. In our data of adult rats, intraduodenally administered bLF was not detected in the blood of LC rats. This point is clearly different from that found in the growing pig. In the present study, small vesicles with bLF-positive membranes were found in the epithelial cytoplasms, and the lamina propria was also strongly positive in the villous apex. These results suggest that LF receptor has the ability to bind bLF on enterocytes in the adult rats. However, a precise transporting mechanism of bound bLF into the lymphatics in the adult rats may be different from pigs. Further investigation is required to clarify this point.
Kawakami & Lönnerdal (1991) have isolated the LF receptor from human foetal and infant small intestines. They mentioned that the dissociation constant (Kd) of humans was found to be less than 1 µM, and that human transferrin did not compete with human LF (hLF) for binding. Similar kinetic studies in piglets have also demonstrated the presence of the LF receptor in this species (Gislason et al. 1993). They mentioned that the LF receptor was found to be specific; hLF, bLF, and pig TF did not bind to the receptor.
To investigate a possible transporting mechanism of bLF into the lymphatic pathway from intestinal lumen, we examined the radio-ligand receptor assay by using a [125I]-bLF as a specific ligand. The Bmax and Kd value in the rat small intestine was 0.24 fmol mg–1 and 23.8 µM, respectively. Recently, Talukder et al. (2003a) reported that the density of the LF receptor in the intestine was markedly different between Peyer's patches and other regions in the adult cow. They mentioned that the Bmax values were 4.7–6.5, 2.6, and 8.1–8.3 nmol mg–1 protein in the small intestine, colon, and Peyer's patches, respectively, and that the Kd values were almost similar among the regions of the small intestine 3.2–3.7 µM, while that in the colon was lower (1.9 µM) than those in the small intestine. The affinity of the LF-receptor in the rat intestine to bLF is about 7-fold lower than that in the adult cow. Although the affinity and Bmax in the adult rat were lower than those in the adult cow, the bLF possibly bound to the epithelial membranes. It was then transported into the lymph flow. The endocytotic vesicles were clearly demonstrated by the immunohistochemical analysis (Fig. 4).
Baker et al. (2002) reported that the surface of the LF molecule has several regions with a high concentration of positive charges, giving it a high isoelectric point (pI 
9). This positive charge is one of the features that distinguish the LF from other members of the TF family. The most striking region of positive charge comprises the N-terminus of the polypeptide chain. This region provides a site for binding heparin (Van Berkel et al. 1997). He & Furmanski (1995) made the unexpected discovery that LF is spontaneously internalized in cells, where it can act directly on the nuclear DNA as a transcription factor. Vogel et al. (2002) further suggested that the lactoferricin region of LF can act as a ‘tugboat’, which pulls the remainder of the LF protein as its cargo through the membrane. This leads to the prediction that the LF should be able to spontaneously cross membranes, although further evidence is required. We cannot exclude the possibility of a non-specific transporting mechanism of LF such as positive charge effect in the rat intestine.
Some physiological effects of LF have been reported, including antibacterial, antifungal, antiviral, antitumour, anti-inflammatory, antinociception, antistress, and immunoregulatory properties. However, the precise mechanism for the transport of LF from intestinal lumen into the general circulation in adults has been unknown. Kuwata et al. (2000) suggested that the ingested LF survives in transit through the gastrointestinal tract of adult rats as partially degraded forms containing the lactoferricin region. Harada et al. (1999b) confirmed that the intraduodenally infused bLF was transferred into systemic circulation in piglets with intact molecular size by using Western blotting. The present study introduces one possibility for explaining the transporting system of LF in adult rats, which is associated with the LF-receptor. The morphological findings in our experiment support the specific transporting mechanism of LF in the intestine. Furthermore, the lymphatic transport of LF may contribute to induce more physiologically effective actions in the whole body, since absorbed LF can arrive at each organ before being trapped by hepatic cells. It has been reported that LF in the circulation is rapidly cleared by hepatic parenchymal cells via a specific receptor dependent mechanism (Prieels et al. 1978; Ziere et al. 1992). Harada et al. (1999b) have reported the possibility of the entero-hepatic circulation of LF in neonatal and weaned piglets. Thus, it is very important to deliver LF to the whole body before cleavage by the liver.
In conclusion, the present study demonstrates that a heterologous protein, bLF, was possibly transported into blood circulation from the intestine in adult rats. The bLF was transported into blood circulation via the lymphatic pathway. Furthermore, the immunohistochemical findings suggest that the bLF is transported via a receptor-mediated transcytotic mechanism, although the affinity and the number of binding sites to bLF in the rat small intestine was lower than other species. These phenomena may contribute to understanding of the mechanism of multiple functions of LF in adult animals.
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References |
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