help button home button Endocrine Society Endocrinology
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Copyright Permission
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Briard, N.
Right arrow Articles by Dutour, A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Briard, N.
Right arrow Articles by Dutour, A.
Endocrinology Vol. 139, No. 6 2662-2669
Copyright © 1998 by The Endocrine Society

ARTICLES

Endotoxin Injection Increases Growth Hormone and Somatostatin Secretion in Sheep

N. Briard1, V. Guillaume, C. Frachebois, M. Rico-Gomez, N. Sauze, C. Oliver and A. Dutour

Laboratoire de Neuroendocrinologie Experimentale (N.B., V.G., C.F., N.S., C.O., A.D.), INSERM U297, Institut Fédératif Jean Roche, 13916 Marseille Cedex 20 France; Service d’Endocrinologie, Maladies Métaboliques et de la Nutrition (V.G., C.F., C.O., A.D), Hôpital Nord, Chemin des Bourrely 13915 Marseille Cedex 20 France; Departamentes de Phisiologia Anatomia y Produccìon Animal (M.R-G.), Facultad Veterinaria, Campus Universitario, 27002 Lugo Spain

Address all correspondence and requests for reprints to: C. Oliver, Laboratoire de Neuroendocrinologie Expérimentale, INSERM U297, Institut Fédératif Jean Roche, Bvd P. Dramard, 13916 Marseille Cedex 20, France.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Endotoxin has been shown to stimulate GH secretion in human and sheep. However, changes in hypothalamic neurohormones involved in the GH regulation by endotoxin have never been studied in vivo. In sheep it is possible to collect hypophysial portal blood (HPB) and quantify GH-releasing hormone (GHRH) and somatostatin (SRIH) secretion under physiological conditions. The purpose of this study was to determine the effect of an acute iv endotoxin administration on the secretion of these peptides in sheep.

Endotoxin induced a sustained increase of GH (x6.2 ± 1.3) in intact rams. This stimulation was delayed and less marked when compared with the hypothalamic-pituitary-adrenal axis. Surprisingly, the GH increase was associated with an important rise of jugular (x10.6 ± 2.4) and portal (x7.9 ± 3) SRIH levels, without a significant GHRH increase. To determine if the portal SRIH increase was a consequence of an increased short feedback of GH, we studied GH response to endotoxin after a previous GHRH injection to deplete the pituitary pools of GH. In that case, despite the absence of increase of GH after endotoxin treatment, SRIH levels was markedly increased. For the first time we have observed an experimental situation in sheep with a simultaneous and closed amplitude increase in jugular and portal SRIH. The source of jugular SRIH is likely the gastrointestinal tract and the increased jugular SRIH release in systemic circulation might be in part responsible for the increase of hypophysial portal SRIH.

Ultimately our results show that endotoxin induced a complex reaction at multiple levels with a specific increase in both portal and peripheral SRIH levels. The surprising association of a lack of change in GHRH release and an increased secretion of SRIH with the increase of GH suggests that the effect of endotoxin on GH axis is mainly a pituitary one. The selective blockade of somatostatin should be useful for a better knowledge of the role of SRIH stimulation in the physiopathology of septic shock.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
THE NEUROENDOCRINE system plays an important role in maintaining homeostasis under a variety of stress conditions including microbial infection and endotoxin shock. Endotoxin, a lipopolysaccharide found as principal component of gram-negative bacteria (LPS), is the main mediator of septic shock (1). When administered in vivo LPS, strongly stimulates the immune system as well as it modulates the secretion of several mediators and hormones. Briefly, LPS induces a rapid increase in plasma concentration of tumor necrosis factor-{alpha} (TNF{alpha}), interleukin 1 (IL-1), and interleukin 6 (IL-6). In turn, endotoxin together with circulating cytokines stimulates prostaglandin E2 (PGE-2) and interleukin production by various tissues including the hypothalamus and the pituitary gland; its action is mediated, at least in part, via CD14, an endotoxin receptor, which has been identified in monocytes, serum (as a soluble form) as well as in brain and in pituitary (2, 3). Changes in the secretion of several hormones have also been observed (4). Several teams have observed that hormonal changes induced by LPS are important and occur at multiple levels. Indeed, LPS increases activity of the hypothalamic-pituitary-adrenal (HPA) axis (5, 6, 7) and decreases TSH (8) and LH (9, 10, 11) secretion. The activation of the pituitary adrenal axis after endotoxin injection is associated with an increased release of both corticotropin releasing hormone (CRH) and arginine vasopressin (AVP) secretion into hypophysial portal blood (7). The gonadal effect of endotoxin and interleukins occurs also at multiple levels (hypothalamic, pituitary and gonadal), the dramatic decrease of LH being associated with a decrease of GnRH gene expression (12, 13). Communications between the immune and endocrine systems are bi-directional and the hormonal changes induced by endotoxin or cytokines can act on the immune system.

The somatotropic axis is also involved in the reaction to endotoxin or cytokines administration. Indeed, GH and insulin-like growth factor I (IGF-1) have been identified in immune competent cells with immunomodulatory properties (14). The administration of endotoxin induces species-dependent effects on GH secretion: indeed, it increases GH secretion in humans (15, 16) and in sheep (17) but decreases it in rats (18) and cattle (19). The mechanisms of action of endotoxin are not clearly understood. The action of endotoxin may be exerted directly at the level of the pituitary gland or indirectly at the level of one or both hypothalamic neurohormones GH-releasing hormone (GHRH) and somatostatin (SRIH), which act respectively as stimulator or inhibitor of GH secretion. In vitro, endotoxin increases basal GH release from dispersed sheep anterior pituitary cells in a time- and dose-dependent manner (17, 20). Moreover, TNF{alpha} in sheep (21) and IL-6 in rats (22) have been shown to act on GH secretion directly at the pituitary level. However, the direct effect of IL-1 on GH secretion from the pituitary gland is unclear with contradictory reports (23, 24, 25). The action of IL-1 at the level of the hypothalamus has been tested in rats. IL-1 stimulates GHRH and SRIH release from hypothalamic explants (26). Furthermore in rats, the increase of GH induced by the intracerebroventricular inject 10 ng of IL-1 is abolished by the immunoneutralisation of GHRH (27).

There are experimental limitations in rodent models and growing interest in a clinical relevant animal model, such as the sheep, for GH regulation (28). In this animal, it is possible to collect hypophysial portal blood (HPB) and quantify the secretion of neurohormones into HPB under physiological conditions. The purpose of this study was to determine the effects of an acute iv administration of endotoxin on jugular GH, portal GHRH, and jugular and portal SRIH plasma levels in intact rams chronically implanted with perihypophysial cannulae.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Animals
Fourteen intact rams (9–11 months old, 40–45 kg BW) from the Merinos Alps breed were obtained from Ecole Nationale Supérieure Agronomique, Domaine du Merle, Salon de Provence (France). Two weeks before the onset of the study, the rams were transferred to the animal room of the laboratory. All experimental procedures were performed in accordance with local animal use regulations; studies were approved by the Faculty Committee on the Use and Care of Animals.

Experimental procedures
Three sets of experiments were carried out successively. For each experiment, endotoxin (Escherichia coli 055: B5: Sigma, St. Louis, MO) was reconstituted in PBS with 0.1% BSA to a stock concentration of 0.1 µg/µl. Body temperature was recorded regularly.

Exp 1. The aim of this experiment was to study the effect of endotoxin on plasma GH levels in intact rams and to compare the chronology of GH changes with those of several components of the hypothalamic-pituitary adrenal (HPA) axis. The animals (n = 6) were housed in individual pens placed immediately adjacent to each other. They were free to sit or to stand, exposed to natural lighting conditions and allowed free access to food and water. An indwelling catheter was inserted into the external jugular vein. On the following day, endotoxin was administered by an iv bolus injection (400 ng/kg) in 2 ml of saline through the jugular cannula, followed by 5 ml of saline as previously described (16). Jugular blood was collected every 15 min during the 2-h period preceding endotoxin injection and during the subsequent 7 h. Blood samples were immediately centrifuged at 4 C for 10 min and the resulting plasma was stored at -20 C until assayed for GH, ACTH, cortisol, and AVP.

Exp 2. The aim of this experiment was to determine the effects of an acute iv endotoxin administration on jugular GH, portal GHRH, and jugular and portal SRIH plasma levels in intact rams chronically implanted with perihypophysial cannulae. Fifteen days before the experiment, four rams were anesthetized and prepared for portal blood sampling under general anesthesia, as previously described (29, 30). A twin cannula was implanted through the transnasal route in front of the long portal vessels, above the anterior pituitary gland. After 14 days, two catheters were inserted in each jugular vein, one catheter for injection of heparin and endotoxin, the other one for collection of peripheral blood. Two animals were placed side to side in two small pens. One day later, heparin (an initial dose of 25,000 IU followed by 5,000 IU every 30 min) was injected and at 0600 h, a needle was inserted into the upper cannula to create a lesion of the hypophysial portal vessels. The resulting portal blood was collected through the lower cannula.

Animals were injected with endotoxin (200 ng/kg) as described above. Portal and jugular blood was collected every 15 min during the 2-h period preceding endotoxin injection and during the subsequent 9 h. Samples were handled as described in Exp 1 until assayed for GH, SRIH, and GHRH.

Exp 3. The aim of this experiment was to determine if the increase of SRIH after endotoxin was due to an increased short feedback of GH on the hypothalamus. Four rams were prepared for portal blood sampling as described above. Two hours after the beginning of the experiment hGHRH(1–44)NH2 (1 µg/kg bw) (Sanofi, Toulouse, France) was administered by iv bolus injection to deplete the intracellular pool of GH and block the GH response to endotoxin. Three hours after hGHRH injection, endotoxin (200 ng/kg) was administered iv as a bolus. Jugular and portal blood were collected every 15 min for 7 h. Samples were handled as described in Exp 1 until assayed for peripheral GH and peripheral and portal SRIH.

Hormone assays
The GH RIA was performed in duplicate using reagents provided by NIADDK, Hormone Distribution Program (Bethesda, MD). oGH-1–4 was used as standard and the least detectable concentration of GH was 0.5 ng/ml plasma: the intra and interassay coefficients of variation (CV) were 7 and 11%, respectively.

Before GHRH and SRIH RIA, peptides were extracted from plasma with 2 vol acetone/20 mM HCl. The SRIH RIA was performed in duplicate in portal and jugular plasma extracts using [125I]-Tyr-somatostatin as radioligand. The antiserum (no. 2044) was a gift from Dr. C. Rougeot (INSERM U207, Paris, France). The intra and interassay CV were 8 and 10%, respectively, and the least detectable concentration was 5 pg/ml plasma. The GHRH RIA was performed in duplicate in portal plasma extracts. oGHRH (Peninsula, St. Helens, Meseyside, UK), labeled with I125 using the lactoperoxydase method, served as radioligand. Antiserum was raised in our laboratory by immunization of rabbits against oGHRH coupled to BSA with glutaraldehyde. Intra and interassay CV were 9 and 11%, respectively, and the least detectable concentration of oGHRH was 10 pg/ml plasma. Both assays have been previously described (31).

Cortisol, ACTH, and AVP levels were measured in extracted plasma according to RIA methods previously described (32). The intraassay coefficients of variations within the measurement range of each assay were: cortisol 4.7%, ACTH 5%, AVP 5.5%. The limits of detection of the assays were 0.5 ng/ml plasma for cortisol, 10 pg/ml plasma for ACTH, 5 pg/ml plasma for AVP.

Statistical analysis
All data are reported as the mean ± SEM. In Exp 2, mean plasma GH, GHRH, and SRIH values were calculated during each 60-min period. In Exp 3, the mean plasma hormone concentrations were calculated for the period of basal secretion (2 h) the period following GHRH iv injection (2 h) the period of return to GH basal secretion (1 h), and the period following endotoxin administration (2 h). All statistical analysis were performed using one-way ANOVA for repeated measures followed by Fisher’s test (with computer program: Statview 512, Brain Power, Inc., Calabasas, CA). P < 0.05 was considered significant.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
In each experiment, the iv administration of endotoxin at the two doses of 400 ng/kg and 200 ng/kg led to increased respiration, intermittent cough and diarrhea, and a lack of alertness to surrounding. High fever (41 to 43 C) was recorded in all animals that lasted for 6 h. However, the general reactions to endotoxin was more pronounced at the dose of 400 ng/kg leading us to half-reduce the dose in Exps 2 and 3.

Exp 1: effect of endotoxin administration on jugular plasma levels of GH, ACTH, AVP, and cortisol
Endotoxin increased plasma GH concentration significantly (x5.9 ± 2.3) (P < 0.01) (Fig. 1Go). This sustained rise in GH concentration peaked 60 min after endotoxin administration. The hypothalamic-pituitary-adrenal axis was also rapidly and significantly activated (Fig. 1Go). This activation occurred earlier and was much more marked than that of GH. Mean plasma ACTH and cortisol levels increased 30 min after endotoxin administration with a maximum during the second hour (x21.4 ± 6.8 for ACTH and x8 ± 1.9 for cortisol). They remained high during the first 5 (ACTH) and 6 (cortisol) h. Jugular AVP levels increased 30 min and peaked 45 min after endotoxin administration (x10.6 ± 3.1); this increase was rapid and transient, lasting for only 2 h.



View larger version (28K):
[in this window]
[in a new window]
  		Figure 1. Effect of an iv injection of endotoxin (400 ng/kg; injection indicated by an arrow) on jugular GH, cortisol, ACTH, and AVP levels. Values represent the mean ± SEM (n = 6). Statistical significance vs. basal values (-60 to 0 min): *, P < 0.05; **, P < 0.01.

 
Exp 2: effect of endotoxin administration on GH, jugular and portal SRIH, and portal GHRH plasma levels
Approximately 75 min after the endotoxin injection, we observed a significant increase in plasma GH levels (x6.2 ± 1.3) (P < 0.01) (Fig. 2Go). A second and major sustained increase in GH concentration was observed 4 h after endotoxin administration (x5.8 ± 0.6). After this second peak, plasma GH levels remained high and did not return to baseline until the end of the experiment. GHRH levels in portal plasma did not change significantly throughout the experiment (67.9 ± 4.3 pg/ml baseline vs. 70.7 ± 5.3 pg/ml after endotoxin). Its secretion was pulsatile, the pulsatility being observed particularly on individual profiles (Fig. 3Go). Approximately 45 min after the endotoxin injection, we observed a marked increase in SRIH levels both in jugular (x10.6 ± 2.4) and hypophysial portal blood (x7.9 ± 3) (Fig. 2Go). The increase in SRIH levels preceded slightly (15 min) the GH increase. The maximal jugular SRIH level was higher, although not significantly different to the maximal portal SRIH level (116.7 ± 15.4 pg/ml vs. 89.1 ± 33.2 pg/ml after endotoxin injection).



View larger version (41K):
[in this window]
[in a new window]
  		Figure 2. Effect of an iv injection of endotoxin (200 ng/kg; injection indicated by an arrow) on mean (± SEM) hourly GH, portal GHRH, and jugular and portal SRIH levels (n = 4). Statistical significance vs. basal: *, P < 0.05; **, P < 0.01.

 


View larger version (31K):
[in this window]
[in a new window]
  		Figure 3. Effect of an iv injection of endotoxin (200 ng/kg; injection indicated by an arrow) on GH, portal GHRH, and jugular and portal SRIH levels in one representative animal.

 
Exp 3: effect of consecutive administration of GHRH and endotoxin on GH and on jugular and portal SRIH
GHRH iv bolus induced as expected a significant increase in plasma GH levels (x18.4 ± 5.9) (P < 0.01) lasting 140 min and, in response to the following endotoxin administration, the jugular GH levels did not change significantly (4.7 ± 0.9 ng/ml in basal vs. 5.4 ± 0.5 ng/ml after endotoxin). But we observed a rapid and marked increase in jugular (x7.7 ± 0.6) and portal (x11.8 ± 4.5) SRIH levels after the endotoxin administration (Fig. 4Go). The maximal jugular SRIH level was slightly but not significantly higher than the maximal portal SRIH level (132.9 ± 39 pg/ml vs. 80.9 ± 15.4 pg/ml).



View larger version (59K):
[in this window]
[in a new window]
  		Figure 4. A, Effect of an iv injection of GHRH (1 mg/kg bw) following by an iv injection of endotoxin (200 ng/kg) (injections indicated by arrows) on GH and jugular and portal SRIH levels. Values represent the mean ± SEM (n = 4). Statistical significance vs. basal values (-60 to 0 min): *, P < 0.05; **, P < 0.01. B, Mean plasma GH and jugular and portal SRIH values during the 2-h period before, the 2 h after GHRH iv injection, the 1-h period of return to GH basal secretion, and the 2 h after endotoxin iv administration (200 ng/kg). Values are expressed as the mean ± SEM (n = 4). Statistical significance vs. basal values: *, P < 0.05; **, P < 0.01.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
We have shown that endotoxin induces a sustained increase of GH release in intact rams and these results are in agreement with the findings of Coleman et al. (17) in wethers. We observed as previously described an important stimulation of the hypothalamic-pituitary-adrenal (HPA) (7). This stimulation is more marked and precedes that of GH, suggesting as discussed below that CRH or cortisol secretion may be involved in the changes of GH secretion. A delayed and long-lasting increase of GH after endotoxin injection has also been recorded in human volunteers injected with low doses of LPS (1–4 ng/kg), the maximum ranging between 15 to 25 ng/ml and occurring 2–4 h after iv injection (15, 16, 33).

Surprisingly, in our experiment, the increase of GH was associated with an important rise of SRIH without a significant increase of GHRH. Our results concerning GHRH are different from the results obtained in rats. No study on GHRH secretion in portal blood has been performed in rats, but the in vitro results have shown an increase of GHRH release from hypothalamic explants (26) induced by IL-1ß. Furthermore, LPS induced an increase in GHRH release from mediobasal hypothalamus that was abolished by CRH antagonist and an interleukin receptor antagonist protein (IRAP) (34). The difference between rats and sheep may be due to the difference of approach, studies in vitro in rats and in vivo in sheep, or to the species difference.

For the first time, we report that endotoxin induces marked and significant rise in both hypophysial portal and peripheral SRIH levels. This increase in portal SRIH is in agreement with a series of in vitro results obtained in rats (26, 34, 35). For instance, IL-1 stimulates SRIH release from acute hypothalamic explants and from diencephalic fetal cells in vitro (26, 34). On the other hand, the effect of IL-1 on SRIH release from mediobasal hypothalamic (MBH) explants is controversial (34, 35) But, in rats, the increase of SRIH has been correlated with a decrease of GH, the suppression of GH secretion by endotoxin being reversed by a pretreatment with an antiserum antisomatostatin (18). In sheep, no results are available on SRIH and GHRH regulation by endotoxin. It has just been shown that endotoxin induced IL-1 gene expression in choroid plexus (36).

The origin of portal SRIH remained to be determined. LPS could, directly or through the stimulation of cytokines synthesis, stimulate SRIH secretion by neurons of the periventricular nucleus (PeV) as shown in rats (26, 35). This effect might be subsequent to or only amplified by the activation of neurons synthesizing CRH. CRH has been shown to stimulate the release of SRIH in vitro (37, 38) and in vivo (39) (increasing SRIH secretion into hypophysial portal blood). To determine if the portal SRIH increase is a consequence of an increased short feedback of GH, we studied the GH response to endotoxin animal whose GH pituitary pool has been depleted by a previous GHRH injection. Under that condition, despite the absence of increase of GH, SRIH levels were markedly increased after endotoxin treatment. Alternately, the increased levels of SRIH in HPB may simply reflect the contribution of peripheral SRIH to the level of SRIH in the hypothalamic-pituitary vasculature. So far, the rate of transfer of SRIH from peripheral circulation to long hypophysial portal has not been investigated.

For the first time, we have observed an experimental situation in sheep with a simultaneous and closed amplitude increase in jugular and portal SRIH levels. During another stressful conditions (a 5-min isolation contention), we have also observed an increase in portal SRIH levels, but no change in jugular SRIH was evidenced (40). An important peripheral SRIH increase has also been demonstrated in rats after endotoxin treatment (41) and in human during septic shock (Chayvialle, personal communication). In pigs, it has been shown that the increase of somatostatin was much higher in the abdominal portal vein than in the aorta or the internal jugular vein throughout the endotoxin infusion period (42). Peripheral SRIH probably arises mainly from the gastrointestinal tract as Taborsky and Ensinck (43) have shown that, in dogs, the pancreas is a minor source of circulating SRIH even when the D pancreatic cells are stimulated. Moreover, in dogs, TNF{alpha} has been shown to regulate somatostatin release from cultured fundic D cells (44). It has been hypothesized that peripheral somatostatin plays in rats an important role in the regulation of glucose levels during endotoxicosis (41). It is well known that somatostatin induces a decrease in intestinal blood flow, capillary surface area, and intestinal consumption. Acting on smooth muscle of both arterioles and precapillary sphincters, it induces a potent vasoconstriction in the intestinal microcirculation (45, 46). During septic shock, severe evolution is associated with metabolic abnormalities, cardiovascular dysfunction, and multiple organ failure mainly related to ischaemia in part due to alterations in regional microcirculatory blood flow (47, 48). The gastrointestinal somatostatin rise could be a worsening factor in the evolution of multiple organ failure during septic shock.

The surprising association of a lack of change in GHRH release and an increased secretion of SRIH with the increase of GH suggests that the effect of endotoxin on GH axis is mainly a pituitary one. In rats, a discordant effect of endotoxin at hypothalamic and pituitary levels has also be found: endotoxin induces an increase of GHRH secretion from hypothalamic explants (results obtained in vitro) contrasting with the in vivo decrease of GH. The important effect at the pituitary level has previously been shown in vitro. Indeed, Coleman et al. (17, 20) have shown that endotoxin stimulates GH release directly from ovine pituitary cultured cells. This increase of GH secretion is associated with an increased GH mRNA content and this effect is mediated through the lipooxygenase pathway.

The administration of LPS induces complex and multiple-step changes in the organism including a stimulation of cytokines release from peripheral macrophages, particularly a rapid increase of TNF{alpha}, IL-1, and IL-6. LPS and peripheral cytokines stimulate PGE-2 production by the central vasculature and regulate hypothalamic neurons (49). LPS as well as circulating cytokines stimulate both synthesis and secretion of pituitary IL-6 as well as they increase the expression of pituitary IL-1ß and binding sites for cytokines. The effect of cytokines on pituitary cells has been extensively studied. In ovine pituitary cells, Nash et al. (21) have shown that TNF{alpha} increase both IL-6 and GH mRNA level, suggesting a paracrine/autocrine role for IL-6 in GH regulation. In rats, IL-6 stimulates GH release together with PRL and LH release from anterior pituitary cells (22). Furthermore, Il-1 receptors have been identified in rat pituitary and mainly on somatotrophs (50, 51). Moreover, endotoxin can have a physiological effect on pituitary cells since Abraham et al. (3) have established the presence of CD14 in cultured pig anterior pituitary cells.

In addition, LPS may increase the number of receptors for GHRH (GHRH-R) at the pituitary level. This effect may be secondary to the increased stimulation of the HPA axis. Indeed, glucocorticoids act directly at the pituitary level as potent stimulators of GHRH-R gene expression inducing a 5.6 ± 0.7-fold increase in GHRH-R mRNA levels (52). Finally, LPS could act on an unknown hypothalamic factor acting as a GH secretagogue. This factor might bind to the new GH-RP receptor that has been recently identified in hypothalamus and pituitary (53). It could explain the effect of endotoxin on GH without increase in GHRH secretion.

To better understand the mechanism of the prolonged effect of endotoxin on GH in sheep, it would be of interest to study its effect on GH receptor (GH-R) as well as on IGF-1 and insulin-like growth factor-binding protein (IGF-BP) levels. Indeed, a decrease of IGF-1 could explain the sustained effect of endotoxin on GH. In addition in rats, IL-1ß and TNF{alpha} to a lesser extent blunt the IGF-1 mRNA response to GH in hepatocyte primary culture. IL-1ß decreases GH-R and GH-binding protein (GH-BP) mRNA levels (54, 55). Similarly, in steers, a reduction in plasma IGF-1 and IGF-BP2 within the first 24 h after endotoxin administration was found (56).

Ultimately, our results show that endotoxin induces a complex reaction at multiple levels with a specific increase in both portal and peripheral SRIH levels. The selective blockade of somatostatin should be useful for a better knowledge of the role of SRIH in the physiopathology of septic shock.


   Acknowledgments
 
Reagents for ovine GH assay were provided by the NIADDK Hormone Distribution Program. The authors express their thanks to Mr. Vincent and his team (ENSA) for their help throughout the study, to Dr. C. Rougeot (INSERM U207, Paris, France) for her kind gift of somatostatin antiserum, S. Rivest, and J. L. Sartin for helpful discussions. The scientific interest and continuous support of B. Tissier (Ipsen, Signes, France) are gratefully acknowledged.


   Footnotes
 
1 Supported by a fellowship from IPSEN France and by Regional Council Provence Alpes Côte d’Azur. Back

Received December 1, 1997.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

  1. Morrison DC, Ryan JL 1987 Endotoxins and disease mechanisms. Annu Rev Med 38:417–432[Medline]
  2. Holst O, Ulmer AJ, Brade H, Flad HD, Rietschel ET 1996 Biochemistry and cell biology of bacterial endotoxins. FEMS Immunol Med Microbiol 16:83–104[CrossRef][Medline]
  3. Abraham EJ, Oberst RD, Hays MP, Chapes SK, Minton JE 1996 Effect of endotoxin on interleukin-6 secretion and messenger ribonucleic acid in porcine anterior pituitary cells. Domest Anim Endocrinol 13:491–501[CrossRef][Medline]
  4. Imura H, Fukata JI 1994 Endocrine-paracrine interaction in communication between the immune and endocrine systems. Activation of the hypothalamic-pituitary-adrenal axis in inflammation. Eur J Endocrinol 130:32–37[Abstract/Free Full Text]
  5. Makara GB, Stark E, Meszaros T 1971 Corticotrophin release induced by Escherichia coli endotoxin after removal of the medial hypothalamus. Endocrinology 88:412–416[Abstract/Free Full Text]
  6. Rivier C, Chizzonite R, Vale W 1989 In the mouse, the activation of the hypothalamic-pituitary-adrenal axis by a lipopolysaccharide (endotoxin) is mediated through interleukin-1. Endocrinology 125:2800–2805[Abstract/Free Full Text]
  7. Dadoun F, Guillaume V, Sauze N, Farisse J, Velut JG, Orsoni JC, Gaillard R, Oliver C 1998 Effect of endotoxin on the hypothalamus pituitary axis in sheep. Eur J Endocrinol 138:193–197[Abstract]
  8. Elson MK, Oken MM, Schafer RB 1982 Effect of endotoxin fever on plasma clearance of thyrotropin and triiodothyronine: concise communications. J Nucl Med 23:241[Abstract/Free Full Text]
  9. Peter AT, Bosu WT, DeDecker RJ 1989 Suppression of preovulatory luteinizing hormone surges in heifers after intrauterine infusions of Escherichia coli endotoxin. Am J Vet Res 50:368–373[Medline]
  10. Rivier C, Vale W 1990 Cytokines act within the brain to inhibit luteinizing hormone secretion and ovulation in the rat. Endocrinology 127:849–856[Abstract/Free Full Text]
  11. Battaglia DF, Bowen JM, Krasa HB, Thrun La, Viguie C, Karsch FJ 1997 Endotoxin inhibits the reproductive neuroendocrine axis while stimulating adrenal steroids: a simultaneous view from hypophyseal portal and peripheral blood. Endocrinology 138:4273–4281[Abstract/Free Full Text]
  12. Rivest S, Lee S, Attardi B, Rivier C 1993 The chronic intracerebroventricular infusion of interleukin-1 alters the activity of the hypothalamic pituitary gonadal axis of cycling rats. Effect on LHRH and gonadotropin biosynthesis and secretion. Endocrinology 133:2424–2430[Abstract/Free Full Text]
  13. Rivier C In the rat, the intracerebroventricular injection of interleukin-1ß or corticotropin-releasing factor-like peptides blunts testicular responsiveness through mechanisms that do not depend on decreased LH secretion. Program of the 79th Annual Meeting of The Endocrine Society, Minneapolis, MN, 1997, p 58 (Abstract S48–2)
  14. Auernhammer CJ, Strasburger CJ 1995 Effects of growth hormone and insulin-like growth factor I on the immune system. Eur J Endocrinol 133:635–645[Abstract/Free Full Text]
  15. Elin RJ, Wolff SM, McAdam KPWJ, Chedid L, Audibert F, Bernard C, Oberling F 1981 Properties of reference Escherichia coli endotoxin and its phthalylated derivative in humans. J Infect Dis 144:329–336[Medline]
  16. Lang CH, Pollard V, Fan J, Traber LD, Traber DL, Frost RA, Gelato MC, Prough DS 1997 Acute alterations in growth hormone-insulin-like growth factor axis in humans injected with endotoxin. Am J Physiol 273:R371–R378
  17. Coleman ES, Elsasser TH, Kemppainen RJ, Coleman DA, Sartin JL 1993 Effect of endotoxin on pituitary hormone secretion in sheep. Neuroendocrinology 58:111–122[Medline]
  18. Kasting NW, Martin JB 1982 Altered release of growth hormone and thyrotropin induced by endotoxin in the rat. Am J Physiol 243:E332–E337
  19. Kenison DC, Elsasser TH, Fayer R 1991 Tumor necrosis factor as a potential mediator of acute metabolic and hormonal responses to endotoxemia in calves. Am J Vet Res 52:1320–1326[Medline]
  20. Coleman ES, Sartin JL 1996 Endotoxin stimulates in vitro pituitary growth hormone release in eicosanoid-dependent manner. Am J Vet Res 57:1662–1667[Medline]
  21. Nash Ad, Malcom R, Bello B 1992 Effects of tumour necrosis factor-{alpha} on growth hormone and interleukin 6 mRNA in ovine pituitary cells. Mol Cel Endocrinol 84:31–37
  22. Spangelo BL, Judd AM, Isakson PC, McLeod RM 1989 Interleukin-6 stimulates anterior pituitary hormone release in vitro. Endocrinology 125:575–577[Abstract/Free Full Text]
  23. Bernton EW, Beach JE, Holaday JW, Smallridge RC, Fein HG 1987 Release of multiple hormones by a direct action of interleukin-1 on pituitary cells. Science 238:519–521[Abstract/Free Full Text]
  24. Uehara A, Gillis S, Arimura A 1987 Effects of interleukin-1 on hormone release from normal rat pituitary cells in primary culture. Neuroendocrinology 45:343–347[Medline]
  25. Kehrer P, Turnill D, Dayer JM, Muller AF, Gaillard RC 1988 Human recombinant interleukin-1 beta and -alpha, but not recombinant tumour necrosis factor alpha stimulate ACTH release from rat anterior pituitary cells in vitro in a protaglandin E2 and cAMP independent manner. Neuroendocrinology 48:160–166[CrossRef][Medline]
  26. Honegger J, Spagnoli A, D’Urso R, Navarra P, Tsagarakis S, Besser GM, Grossman AB 1991 Interleukin-1ß modulates the acute release of growth hormone releasing hormone and somatostatin from rat hypothalamus in vitro, whereas tumor necrosis factor and interleukin-6 have no effect. Endocrinology 129:1275–1282[Abstract/Free Full Text]
  27. Payne LC, Obal F, Opp MR, Krueger JM 1992 Stimulation and inhibition of growth hormone secretion by interleukin-1ß: the involvement of growth hormone releasing hormone. Neuroendocrinology 56:118–123[Medline]
  28. Dutour A, Briard N, Guillaume V, Magnan E, Cataldi M, Sauze N, Oliver C 1997 Another view of GH neuroregulation: lessons from the sheep. Eur J Endocrinol 136:553–565[Abstract/Free Full Text]
  29. Locatelli A, Caraty A 1987 Approche transnasale du système porte-hypophysaire chez le bélier: application à l’étude des neuro-sécrétions. Sci Tech Anim Lab 12:185–190
  30. Caraty A, Grino M, Locatelli A, Oliver C 1988 Secretion of corticotropin-releasing factor (CRF) and vasopressin (AVP) into the hypophysial portal blood of conscious, unrestrained rams. Biochem Biophys Res Commun 155:841–849[CrossRef][Medline]
  31. Magnan E, Cataldi M, Guillaume V, Mozzochi L, Dutour A, Conte-Devolx B, Giraud P, Oliver C 1993 Neostigmine stimulates growth hormone-releasing hormone release into hypophysial portal blood of conscious sheep. Endocrinology 132:1247–1251[Abstract/Free Full Text]
  32. Caraty A, Grino M, Locatelli A, Guillaume V, Boudouresque F, Conte-Devolx B, Oliver C 1990 Insulin-induced hypoglycemia corticotropin-releasing factor and arginine vasopressin secretion into hypophysial portal blood of conscious, unrestrained rams. J Clin Invest 85:1716–1721
  33. Bloesch D, Keller U, Spinas GA, Küry D, Girard J, Stauffacher W 1993 Effects of endotoxin on leucine and glucose kinetics in man: contribution of prostaglandin E2 assessed by a cyclooxygenase inhibitor. J Clin Endocrinol Metab 77:1156–1163[Abstract]
  34. Peisen JN, McDonnell KJ, Mulroney SE, Lumpkin MD 1995 Endotoxin-induced suppression of the somatotropic axis is mediated by interleukin-1ß and corticotropin releasing factor in the juvenile rat. Endocrinology 136:3378–3390[Abstract]
  35. Scarborough DE, Lee SL, Dinarello CA, Reichlin S 1989 Interleukin-1ß stimulates somatostatin biosynthesis in primary cultures of fetal rat brain. Endocrinology 124:549–551[Abstract/Free Full Text]
  36. Vellucci SV, Parrott RF 1996 Bacterial endotoxin-induced gene expression in the choroid plexus and paraventricular and supraoptic hypothalamic nuclei of the sheep. Mol Brain Res 43:41–50[Medline]
  37. Aguila MC, McCann SM 1985 The influence of hGRF, CRF, TRH, and LHRH on SRIF release from median eminence fragments. Brain Res 348:180–182[CrossRef][Medline]
  38. Peterfreund RA, Vale WW 1983 Ovine corticotropin-releasing factor stimulates somatostatin secretion from cultured brain cells. Endocrinology 112:1275–1278[Abstract/Free Full Text]
  39. Mitsugi N, Arita J, Kimura F 1990 Effects of intracerebroventricular administration of growth hormone-releasing factor and corticotropin-releasing factor on somatostatin secretion into rat hypophysial portal blood. Neuroendocrinology 51:93–96[CrossRef][Medline]
  40. Cataldi M, Magnan E, Guillaume V, Dutour A, Mazzochi L, Giraud P, Conte-Devolx B, Oliver C 1994 Acute stress stimulates secretion of GHRH and somatostatin into hypophysial portal blood of conscious sheep. Neurosci Lett 178:103–106[CrossRef][Medline]
  41. Yelich MR, Umporowicz DM, Drolet BA 1993 Role of somatostatin in glucose regulation during endotoxicosis in the rat. Am J Physiol 264:R254–R261
  42. Revhaug A, Lygren I, Lundgren TI, Jorde R, Burhol PG, Giercksky KE 1984 Release of gastrointestinal peptides during E. coli endotoxinaemia. Acta Chir Scand 150:535–539[Medline]
  43. Taborsky GJ, Ensinck JW 1984 Contribution of the pancreas to circulating somatotstatin-like immunoreactivity in the normal dog. J Clin Invest 73:216–223
  44. Beales I, Calam J, Post L, Srinivasan S, Yamada T, Delvalle J 1997 Effect of transforming growth factor {alpha} and interleukin-8 on somatostatin release from canine fundic D cells. Gastroenterology 112:136–143[CrossRef][Medline]
  45. Pawlik WW, Gustaw P, Czarnobilski K, Sendur R, Konturek SJ 1989 Effects of somatostatin on intestinal circulation and oxygen consumption. Acta Phys Hung 74:277–283
  46. Romeo JM, Novo C, Fernandez-Cruz A, Lopez-Novoa JM 1990 Hemodynamic effects of somatostatin in the rat: relationship with plasma glucagon levels. Heart Vessels 5:219–223[CrossRef][Medline]
  47. Rackow EC, Astik ME 1991 Pathophysiology and treatment of septic shock. JAMA 266:548–554[Abstract/Free Full Text]
  48. Livingston DH, Mosenthal AC, Deitch EA 1995 Sepsis and multiple organ dysfunction syndrome: a clinical-mechanistic overview. New Horizons 3:257–266[Medline]
  49. Abraham EJ, Minton JE 1997 Cytokines in the hypophysis: a comparative look at interleukin-6 in the porcine anterior pituitary gland. Comp Biochem Phys 116:203–207[CrossRef]
  50. Marquette C, Van Dam AM, Ban E, Lanièce P, Crumeyrolle-Arias M, Fillion G, Berkenbosch F, Haour F 1995 Rat interleukin-1ß binding sites in rat hypothalamus and pituitary gland. Neuroendocrinology 62:362–369[Medline]
  51. French RA, Zachary JF, Dantzer R, Frawley LS, Chizzonite R, Parnet P, Kelley KW 1996 Dual expression of p80 type I and p68 type II interleukin-I receptors on anterior pituitary cells synthesizing growth hormone. Endocrinology 137:4027–4036[Abstract]
  52. Korytko AI, Cuttler L 1997 Thyroid hormone and glucocorticoid regulation of pituitary growth hormone-releasing hormone receptor gene expression. J Endocrinol 152:R13–R17
  53. McKee KK, Palyha OC, Feighner SD, Hreniuk DL, Tan CP, Phillips MS, Smith RG, Van der Ploeg LHT, Howard AD 1997 Molecular analysis of rat pituitary and hypothalamus growth hormone secretagogue receptors. Mol Endocrinol 11:415–423[Abstract/Free Full Text]
  54. Thissen JP, Verniers J 1997 Inhibition by interleukin-1ß and tumor necrosis factor-{alpha} of the insulin-like growth factor I messenger ribonucleic acid response to growth hormone in rat hepatocyte primary culture. Endocrinology 138:1078–1084[Abstract/Free Full Text]
  55. Wolf M, Böhm S, Brand M, Kreymann G 1996 Proinflammatory cytokines interleukin 1ß and tumor necrosis factor {alpha} inhibit growth hormone stimulation of insulin-like growth factor I synthesis and growth hormone receptor mRNA levels in cultured rat liver cells. Eur J Endocrinol 135:729–737[Abstract/Free Full Text]
  56. Elsasser TH, Caperna TJ, Rumsey TS 1995 Endotoxin administration decreases plasma insulin-like growth factor (IGF)-I and IGF-binding protein-2 in Angus x Hereford steers independent of changes in nutritional intake. J Endocrinol 144:109–117[Abstract/Free Full Text]



This article has been cited by other articles:


Home page
 J ANIM SCIHome page
J. A. Carroll
Bidirectional communication: Growth and immunity in domestic livestock
J Anim Sci, April 1, 2008; 86(14_suppl): E126 - E137.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Endocrinol. Metab.Home page
J. A. Daniel, T. H. Elsasser, A. Martinez, B. Steele, B. K. Whitlock, and J. L. Sartin
Interleukin-1{beta} and tumor necrosis factor-{alpha} mediation of endotoxin action on growth hormone
Am J Physiol Endocrinol Metab, October 1, 2005; 289(4): E650 - E657.
[Abstract] [Full Text] [PDF]

Home page
 J EndocrinolHome page
C Viguie, Y Chilliard, V Gayrard, N Picard-Hagen, P Monget, A Dutour, and P-L Toutain
Alterations of somatotropic function in prion disease in sheep
J. Endocrinol., November 1, 2004; 183(2): 427 - 435.
[Abstract] [Full Text] [PDF]

Home page
 J. Clin. Endocrinol. Metab.Home page
D. Seboek, P. Linscheid, H. Zulewski, I. Langer, M. Christ-Crain, U. Keller, and B. Muller
Somatostatin Is Expressed and Secreted by Human Adipose Tissue upon Infection and Inflammation
J. Clin. Endocrinol. Metab., October 1, 2004; 89(10): 4833 - 4839.
[Abstract] [Full Text] [PDF]

Home page
 J. Immunol.Home page
M. Delgado, C. Martinez, D. Pozo, J. R. Calvo, J. Leceta, D. Ganea, and R. P. Gomariz
Vasoactive Intestinal Peptide (VIP) and Pituitary Adenylate Cyclase-Activation Polypeptide (PACAP) Protect Mice from Lethal Endotoxemia Through the Inhibition of TNF-{alpha} and IL-6
J. Immunol., January 15, 1999; 162(2): 1200 - 1205.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Copyright Permission
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Briard, N.
Right arrow Articles by Dutour, A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Briard, N.
Right arrow Articles by Dutour, A.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Endocrinology Endocrine Reviews J. Clin. End. & Metab.
Molecular Endocrinology Recent Prog. Horm. Res. All Endocrine Journals