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Regulation of the growth hormone and luteinizing hormone response to endotoxin in sheep
Domestic Animal Endocrinology 23 (2002) 361–370
Regulation of the growth hormone and luteinizing hormone response to endotoxin in sheep J.A. Daniel, B.K. Whitlock, C.G. Wagner, J.L. Sartin∗ Department of Anatomy, Physiology, and Pharmacology, College of Veterinary Medicine, Auburn University, Auburn, AL 36849, USA
Abstract Infectious disease processes cause physiological adaptations in animals to reorder nutrient partitioning and other functions to support host survival. Endocrine, immune and nervous systems largely mediate this process. Using endotoxin injection as a model for catabolic disease processes (such as bacterial septicemia), we have focused our attention on regulation of growth hormone (GH) and luteinizing hormone (LH) secretion in sheep. Endotoxin produces an increase in plasma GH and a decrease in plasma LH concentrations. This pattern can be reproduced, in part, by administration of various cytokines. Antagonists to both interleukin-1 (IL-1) and tumor necrosis factor (TNF) given intravenously (IV) prevented the endotoxin-stimulated increase in GH. Since endotoxin will directly stimulate GH and LH release from cultured pituitary cells, the data suggest a pituitary site of action of the endotoxin to regulate GH. Studies with portal vein cannulated sheep indicated that gonadotropin releasing hormone was inhibited by endotoxin, suggesting a central site of action of endotoxin to regulate LH. However, other studies suggest that endotoxin may also regulate LH secretion at the pituitary. Thus, IL-1 and TNF regulate GH release from the pituitary gland while endotoxin induces a central inhibition of LH release. © 2002 Elsevier Science Inc. All rights reserved.
1. Introduction When faced with an infectious disease challenge, an animal responds with numerous mechanisms to insure survival. The immune system components are activated, endocrine system responses favor catabolic actions, nutrients are repartitioned, and less essential functions ∗
Corresponding author. Present address: 214 Greene Hall, Auburn University, Auburn, AL 36849, USA. Tel.: +1-334-844-5515; fax: +1-334-844-5388. E-mail address: [email protected] (J.L. Sartin). 0739-7240/02/$ – see front matter © 2002 Elsevier Science Inc. All rights reserved. PII: S 0 7 3 9 - 7 2 4 0 ( 0 2 ) 0 0 1 7 1 - 6
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such as reproduction and growth are suspended. Although many different types of infectious diseases exist and the specific response to differing diseases may vary, some of the mechanisms by which the animal shifts nutrients from growth and reproduction to immune function are likely consistent across various diseases. In the study of the response to disease, it is often useful to utilize models of the disease process as opposed to the disease itself. One model for disease that is commonly used is the administration of endotoxin or lipopolysaccharide (LPS). The presence of endotoxin, a component of the cell wall of gram negative bacteria, has been implicated in septicemia, a cause of 175,000–200,000 deaths annually in the United States [1,2].
2. Effect of endotoxin on cytokine production The effects of endotoxin have been studied in many domestic animals as well as humans and rodents. Following exposure to endotoxin, there is an increase in circulating concentration of a number of cytokines including tumor necrosis factor (TNF), interleukin-1 (IL-1), and interleukin-6 (IL-6) [3]. These cytokines are involved in numerous responses to endotoxin including fever, hypophagia, and general inflammation. Investigations of induction of cytokine production by endotoxin have been limited in sheep. However, intravenous (IV) bolus endotoxin administration resulted in increased TNF activity in the plasma [4] and an increase in plasma concentration of TNF in the sheep [5,6]. Endotoxin administration also increased IL-1 mRNA expression in the choroid plexus of sheep [7]. Some of these cytokines may mediate the effects of endotoxin to regulate the secretion of pituitary hormones in sheep.
3. Endotoxemia and growth hormone Growth hormone (GH) is involved with regulation of metabolism, either directly as in fat catabolism or indirectly as in protein synthesis via insulin-like growth factor-I (IGF-l). In addition, GH has a role in immune modulation. For example, cells of the immune system synthesize GH after exposure to endotoxin [8]. Moreover, GH has profound effects to improve the response of cattle treated with endotoxin [9]. Thus, effects of GH on metabolism and on immune function suggest a critical regulatory event in the animals’ response to sepsis or endotoxemia. 3.1. Endotoxin inhibition of GH—birds, cattle, rats The endotoxin model for study of GH release has been used in a number of species with varied results. Growth hormone release in response to injection of E. coli endotoxin is reduced in birds, cattle, and rodent models [9,10,11], which is paralleled by changes in IGF-l (rats [12]; cattle [13]). Similar effects to those seen with endotoxin were obtained when using cytokines. For example, TNF inhibited GH releasing hormone (GRH)-stimutated GH release from cultured rat pituitary cells [14,15] and cattle pituitary cells in vitro and in vivo [16,17]. Pituitary cells cultured with IL-1 had an increased release of GH [18] while IL-1 stimulated GH
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release following intracerebroventricular (ICV) injection [19,20] at low but not high doses [19]. IL-1 was also reported to inhibit GH surges by either IV or ICV injection [21]. Moreover, IL-1 receptor antagonist infused ICV followed by IV injection of endotoxin prevented the effects of endotoxin to inhibit GH release, indicating a role for IL-1 in the endotoxin inhibition of GH release [22]. The effects of endotoxin to reduce plasma concentrations of GH in rats were suggested to be via a hypothalamic mechanism because: (1) GH inhibition was reversed by use of somatostatin (SS) antiserum [11]; (2) endotoxin elevated hypothalamic SS content [23]; and (3) IL-1 stimulated SS release from cultured fetal neurons [24]. 3.2. Endotoxin stimulation of GH—sheep, pigs, humans Data for sheep, pigs, and humans [5,25,26] indicate that plasma GH concentrations are increased by endotoxin. In contrast to the GH response, endotoxin inhibits IGF-1 in these species [27,28,29]. However, the mechanism and site of action for these different effects on GH release in these models are not known. The effect of endotoxin to increase plasma GH concentrations in sheep was delayed in time of onset and persisted for more than 8 h (Fig. 1; [5]). Moreover, the effects of endotoxin to release GH in sheep were found to be reproduced in vitro using cultured pituitary cells [5]. The effects of endotoxin on in vitro or in vivo GH release were not influenced by the subsequent treatment with GRH [5]. This led to a hypothesis that the effects of endotoxin occurred at the level of the pituitary (rather than the hypothalamus as seen in rats). Possibilities considered were that endotoxin increased cytokine production outside the pituitary (macrophages) which in turn altered GH release, endotoxin stimulated directly the production of cytokines from the
Fig. 1. Endotoxin stimulated increase in plasma concentrations of growth hormone. Endotoxin was administered IV at 0.4 g/kg BW. N = 5 for control and n = 5 for endotoxin. Treatment effect, P < 0.01; [5].
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pituitary to subsequently alter GH release, or endotoxin had a direct effect on somatotrope to increase GH release [5]. Two different types of experiments were employed to determine the site of action of endotoxin on GH release in sheep. One approach [30] utilized portal vein cannulated sheep to determine whether GH release by endotoxin was a result of increased secretion of GH releasing hormone or reduced secretion of SS. Their data indicated that GRH release was unchanged while SS release was actually increased in the sheep, similar to the effect of endotoxin to increase SS in the rat. However, unlike the rat, these hypothalamic releasing factors were not likely responsible for the effects of endotoxin to increase GH release. Moreover, these data argued in favor of a pituitary site of action or another form of hypothalamic mediation of the endotoxin effect on GH. Clearly this mechanism does not account for the increase in plasma GH in sheep. Finally, Vellucci et al. [31] found that IL-1 injected ICV increased plasma cortisol concentrations and increased temperature but had no effect on plasma GH, suggesting little or no central site of action of low doses of IL-1 in mediating GH release in response to endotoxin. In the second experimental approach, Nash et al. [32] determined that TNF increased GH and interleukin-6 (IL-6) mRNA in cultured sheep pituitary cells. Studies by Fry et al. [33] determined the effects of specific cytokines on GH release from cultured sheep pituitary cells. These data provided evidence that interleukin-2 and interferon-␥ had no effects on GH release in vitro in sheep, though both cytokines inhibit GH release from cultured rat pituitary cells [34,35]. As determined for cattle [36], TNF inhibited GRH-stimulated GH release in cultured sheep pituitary cells but had no effect on basal GH release in the sheep [33]. Messenger RNA levels were not determined in this study, but the data suggest even if synthesis were increased by TNF as was described by Nash et al. [32], secretion of GH from these cultured cells did not increase. In view of the effects of TNF to increase IL-6 mRNA [32], attempts were also made to determine whether human IL-6 had an effect on secretion of GH, but there appeared to be no effects, perhaps due to species differences in the IL-6 molecule [33]. However, IL-1 and IL-l␣ both stimulated GH release and IL- increased GH mRNA production and pituitary GH content [33]. GRH had no effects on IL-1-stimulated GH release while SS inhibited both IL-l␣and IL-l-stimulated release of GH. Moreover, the effects on GH release were determined to be mediated via protein kinase A, Ca2+ dependent mechanisms, and the cyclooxygenase pathway. Interestingly, endotoxin effects on GH release were also found to be mediated via the cyclooxygenase pathway, though whether this was an effect directly on the somatotrope to release GH or an effect on GH release mediated through pituitary cytokine production was not determined [33,37].Current studies have been designed to determine the role of IL-1 and TNF in the regulation of GH. These preliminary studies have found that IV injection of both TNF and IL-1 will increase plasma concentrations of GH. In addition, IV injection of human IL-1 receptor antagonist and human soluble TNF receptor (Amgen Inc., Thousand Oaks, CA) will inhibit the effects of endotoxin on GH release [38]. These studies combined with previous data suggest a role for both IL-1 and TNF in regulating the plasma concentrations of GH. Moreover, the data from these studies indicate an effect of endotoxemia that is in part mediated via cytokines at the level of the pituitary gland. Other factors may also play a role in this process but have not been critically examined in the context of endotoxemia. Cortisol release is stimulated by endotoxin and may play a role
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in models of endotoxin reduced GH release. Moreover, cortisol inhibition of GH is observed in a time frame consistent with endotoxin stimulation of cortisol [39,40]. Cortisol may have a role in GH inhibition by endotoxin in rodent models; but if cortisol participates in the endotoxin effect in sheep, it may blunt the effects of endotoxin on GH release but is not likely a mediator for increased GH release. Another factor may be the prolonged decrease in plasma IGF concentrations producing a reduced negative feedback on GH. However, reduced IGF is present in both endotoxin-stimulated GH (sheep) and in models such as cattle and rats, where plasma GH concentrations are reduced. Also, IGF-l changes are slow to develop and probably do not account for increased GH in the sheep. 4. Endotoxemia and LH secretion Multiple investigators have demonstrated that endotoxin causes a decrease in plasma concentration and pulse frequency of LH in the sheep (Fig. 2; [5,41,42]. Battaglia and co-workers also demonstrated that endotoxin disrupted the estradiol induced LH surge following progesterone withdrawal in intact ewes [43,44]. Indirect and direct evidence suggests that endotoxin suppresses LH secretion at the level of the hypothalamus. In experiments examining hypophyseal portal blood, Battaglia and co-workers observed that endotoxin administered IV decreased pulsatile GnRH [41]. Providing further evidence that endotoxin is acting at the level of the brain to suppress LH secretion, Battaglia and co-workers also observed that endotoxin blocks the initial estradiol signaling to the brain to initiate the LH surge and not surge release [43]. Additionally, in vitro endotoxin stimulated an increase in media accumulation of LH from cultured pituitary cells [5], and both
Fig. 2. Endotoxin suppressed plasma concentration of luteinizing hormone. N = 5 per treatment group. LH was reduced from 1–6 h after endotoxin, P < 0.01. There was a reduction in number of LH pulses, P < 0.05; [5].
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IL-1␣ and IL-1 stimulated an increase in media concentration of LH from cultured pituitary cells, although IL-2, TNF, and interferon-␥ did not effect LH concentration [45]. Cumulatively, these data suggest that endotoxin suppresses LH secretion in vivo at the level of the hypothalamus. However, other data suggest that endotoxin may suppress LH secretion at the level of the pituitary. Endotoxin appeared to uncouple GnRH and LH pulse patterns [41,42]. Furthermore, endotoxin suppressed pituitary responsiveness to exogenous GnRH [2]. These data suggest that endotoxin may also affect LH secretion at the level of the pituitary in addition to the inhibitory actions at the hypothalamus. Endotoxin suppression of LH may occur through activation of the stress induced hypothalamic–pituitary–adrenal axis. Stress is generally considered to be detrimental to reproduction. Administration of endotoxin IV resulted in increased circulating cortisol and ACTH as well as increased hypophyseal portal blood concentrations of corticotropin-releasing hormone (CRH) and arginine vasopressin (AVP) [46], and increased concentrations of AVP in the cerebrospinal fluid and plasma [47]. The increase in hypophyseal portal blood concentrations of CRH and AVP stimulated by endotoxin corresponds temporally with decreased hypophyseal portal blood concentrations of GnRH and circulating LH [48]. Central administration of recombinant human IL-1 also increased body temperature, circulating concentration of cortisol, and expression of c-fos mRNA in the paraventricular nucleus and supracoptic nucleus, and CRH mRNA in the PVN [31]. However, central administration of CRH has been demonstrated
Fig. 3. Schematic illustration of possible mechanisms by which endotoxin may increase growth hormone concentrations in sheep. Solid arrows indicate pathways for endotoxin regulation of GH release that are substantiated by the data. The dotted arrows indicate pathways that may exist but are not primary pathways for GH regulation.
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to stimulate an increase in LH secretion in intact ewes and castrated rams [49,50]. Additionally, central administration of AVP did not affect LH secretion [50]. Thus, it is unlikely that the endotoxin-induced stress response is mediating the suppressive effects of endotoxin on LH in sheep. Endotoxin may be acting through the production of cytokines to inhibit LH secretion. The cytokines could arise from either peripheral monocytes or be produced by the hypothalamus or pituitary in response to endotoxin. Administration of cytokines can mimic some of the effects of endotoxin. Administration of recombinant human TNF to lambs included fever and caused a significant increase in plasma concentrations of cortisol, glucagon, and insulin [51]. Central administration of recombinant human IL-1 increased IL-1 mRNA expression in the PVN and in the cells bordering the third ventricle in sheep [31]. These cytokines could then act directly or through mediators such as prostaglandins to inhibit LH secretion. However, central administration of IL-1 did not affect circulating concentrations of prolactin or GH nor expression of AVP mRNA in the PVN and SON [31]. Evidence suggests that prostaglandins may mediate endotoxin suppression of LH secretion. Administration of the prostaglandin synthesis inhibitor, flurbiprofen, prevented endotoxin suppression of LH and GnRH secretion and stimulation of fever but did not prevent the rise in TNF observed following endotoxin administration [52]. However, the endotoxin reduced pituitary responsiveness to exogenous GnRH was not altered by the prostaglandin inhibitor, flurbiprofen [42]. Thus, although it is clear that endotoxin inhibits LH secretion, the complete mechanism by which endotoxin inhibits LH secretion is not yet clear.
Fig. 4. Schematic illustration of possible mechanisms by which endotoxin may decrease luteinizing hormone concentrations in sheep. Arrows indicate primary pathways for LH regulation by endotoxin.
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5. Summary Although not conclusive, the data suggest that endotoxin stimulates increased plasma concentration of GH in sheep at the level of the pituitary (Fig. 3), perhaps via effects of TNF or IL-1. In contrast, endotoxin suppresses plasma concentration of LH in the sheep at the level of the hypothalamus (Fig. 4), although some data do suggest that the ability of the pituitary to respond to GnRH is reduced.
Acknowledgments This work was supported by USDA NRI Grant 99-03361 and Amgen, Inc. References [1] Hoffman WD, Natanson C. Endotoxin in septic shock. Anesth Analg 1993;77:613–24. [2] Ulevitch RJ, Tobias PS. Receptor-dependent mechanisms of cell stimulation by bacterial endotoxin. Annu Rev Immunol 1995;13:437–57. [3] Janeway CA, Travers P. Immunobiology The immune system in health and disease. New York: Current Biology Ltd./Garland Publishing Inc., 1997. [4] Bieniek K, Szuster-Ciesielska A, Kamiñska T, Kondracki M, £okaj I, Kandefer-Szerszeñ M. Interferon and tumor necrosis factor production during endotoxemia in sheep. Archivum lmmunologiae et Therapiae Experimentalis 1998;46:105–11. [5] Coleman ES, Elsasser TH, Kemppainen RJ, Coleman DA, Sartin JL. Effect of endotoxin on pituitary hormone secretion in sheep. Neuroendocrinology 1993;58:111–22. [6] Perkowski SZ, Sloane PJ, Spath Jr JA, Elsasser TH, Fisher JK, Gee MH. TNF-␣ and the pathophysiology of endotoxin-induced acute respiratory failure in sheep. J Appl Physiol 1996;80(2):564–73. [7] Vellucci SV, Parrott RF. Bacterial endotoxin-induced gene expression in the choroid plexus and paraventricular and supraoptic hypothalamic nuclei of the sheep. Mol Brain Res 1996;43:41–50. [8] Weigent DA, Blalock JE. The production of growth hormone by subpopulations of rat mononuclear leukocytes. Cell Immunol 1991;135:55–65. [9] Elsasser TH, Fayer R, Rumsey TS, Hartnell GF. Recombinant bovine somatotropin blunts plasma tumor necrosis factor-alpha, cortisol, and thromboxane-B2 responses to endotoxin in vivo. Endocrinology 1992;134:1082–8. [10] Curtis MJ, Flack IH, Harvey S. The effect of Escherichia coli endotoxins on the concentrations of corticosterone and growth hormone in the plasma of the domestic fowl. Res Vet Sci 1980;28:123–7. [11] Kasting NW, Martin JB. Altered release of growth hormone and thyrotropin induced by endotoxin in the rat. Am J Physiol 1982;243:E332–7. [12] Fan J, Char D, Bagby GJ, Gelato MC, Lang CH. Regulation of insulin-like growth factor-I (IGF-l) and IGF-binding proteins by tumor necrosis factor. Am J Physiol 1995;269:1204–12. [13] Elsasser TH, KahI S, Rumsey TS, Blum JW. Modulation of growth performance in disease: reactive nitrogen compounds and their impact on cell proteins. Domest Anim Endocrinol 2000;19:75–84. [14] McCann SM, Rettori V, Milenkovic L, Jurcovicoa J, Gonzalez MC. Role of monokines in control of anterior pituitary hormone release. Adv Exp Med Biol 1990;274:315–29. [15] Gaillard MJ, Turnhill D, Sappino P, Muller AF. Tumor necrosis factor alpha inhibits the hormonal response of the pituitary gland to hypothalamic releasing factors. Endocrinology 1990;127:101–6. [16] Elsasser TH, Caperna TJ, Fayer R. Tumor necrosis factor-alpha affects growth hormone secretion by a direct pituitary interaction. Proc Soc Exp Biol Med 1991;198:546–54.
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[40] Sartin JL, Kemppainen RJ, Coleman ES, Steele B, Williams JC. Cortisol inhibition of growth hormonereleasing hormone-stimulated growth hormone release from cultured sheep pituitary cells. J Endocrinol 1994;141:517–25. [41] Battaglia DF, Bowen JM, Krasa HB, Thrun LA, Viguié C, Karsch FJ. Endotoxin inhibits the reproductive neuroendocrine axis while stimulating adrenal steroids: a simultaneous view from hypophyseal portal and peripheral blood. Endocrinology 1997;138:4273–81. [42] Williams CY, Harris TG, Battaglia DF, Viguié C, Karsch FJ. Endotoxin inhibits pituitary responsiveness to gonadotropin-releasing hormone. Endocrinology 2001;142:1915–22. [43] Battaglia DF, Beaver AB, Harris TG, Tanhehco E, Viguié C, Karsch FJ. Endotoxin disrupts the estradiolinduced luteinizing hormone surge; interference with estradiol signal reading, not surge release. Endocrinology 1999;140:2471–9. [44] Battaglia CF, Krasa HB, Padmanabhan V, Viguié E, Karsch FJ. Endocrine alterations that underlie endotoxin-induced disruptions of the follicular phase in ewes. Biol Reprod 2000;62:45–53. [45] Braden ID, Fry C, Sartin JL. Effects of inerleukins on secretion of luteinizing hormone from ovine pituitary cells. Am J Vet Res 1998;59:1488–93. [46] Dadoun F, Guillaume V, Sauze N, Farisse J, Velut JG, Orsoni JC, Gaillard R, Oliver C. Effect of endotoxin on the hypothalamic–pituitary–adrenal axis in sheep. Eur J Endocrinol 1998;138:193–7. [47] Kasting NW, Carr DB, Martin JB, Blume H, Bergland R. Changes in cerebrospinal fluid and plasma vasopressin in the febrile sheep. Can J Physiol Pharmacol 1993;61:427–31. [48] Battaglia DF, Brown ME, Krasa HB, Thrun LA, Viguié C, Karsch FJ. Systemic challenge with endotoxin stimulates corticotropin-releasing hormone and arginine vasopressin secretion into hypophyseal portal blood: coincidence with gonadotropin-releasing hormone suppression. Endocrinology 1998;139:4175–81. [49] Naylor AM, Porter DWF, Lincoln DW. Central administration of corticotrophin-releasing factor in the sheep: effects on secretion of gonadotrophins, prolactin and cortisol. J Endocrinol 1990;124:117–25. [50] Tilbrook AJ, Canny BJ, Stewart BJ, Serapiglia MD, Clarke IJ. Central administration of corticotrophin releasing hormone but not arginine vasopressin stimulates the secretion of luteinizing hormone in rams in the presence and absence of testosterone. J Endocrinol 1999;162:301–11. [51] Douglas RG, Gluckman PD, Breier BH, McCall JL, Parry B, Shaw JHF. Effects of recombinant IGF-l on protein and glucose metabolism in rTNF-infused lambs. Am J Physiol 1991;261:E606–12. [52] Harris TG, Battaglia DF, Brown ME, Brown MB, Carlson NE, Viguié C, Williams CY, Karsch FJ. Prostaglandins mediate the endotoxin-induced suppression of pulsatile gonadotropin-releasing hormone and luteinizing hormone secretion in the ewe. Endocrinology 2000;141:1050–8.
Regulation of the growth hormone and luteinizing hormone response to endotoxin in sheep J.A. Daniel, B.K. Whitlock, C.G. Wagner, J.L. Sartin∗ Department of Anatomy, Physiology, and Pharmacology, College of Veterinary Medicine, Auburn University, Auburn, AL 36849, USA
Abstract Infectious disease processes cause physiological adaptations in animals to reorder nutrient partitioning and other functions to support host survival. Endocrine, immune and nervous systems largely mediate this process. Using endotoxin injection as a model for catabolic disease processes (such as bacterial septicemia), we have focused our attention on regulation of growth hormone (GH) and luteinizing hormone (LH) secretion in sheep. Endotoxin produces an increase in plasma GH and a decrease in plasma LH concentrations. This pattern can be reproduced, in part, by administration of various cytokines. Antagonists to both interleukin-1 (IL-1) and tumor necrosis factor (TNF) given intravenously (IV) prevented the endotoxin-stimulated increase in GH. Since endotoxin will directly stimulate GH and LH release from cultured pituitary cells, the data suggest a pituitary site of action of the endotoxin to regulate GH. Studies with portal vein cannulated sheep indicated that gonadotropin releasing hormone was inhibited by endotoxin, suggesting a central site of action of endotoxin to regulate LH. However, other studies suggest that endotoxin may also regulate LH secretion at the pituitary. Thus, IL-1 and TNF regulate GH release from the pituitary gland while endotoxin induces a central inhibition of LH release. © 2002 Elsevier Science Inc. All rights reserved.
1. Introduction When faced with an infectious disease challenge, an animal responds with numerous mechanisms to insure survival. The immune system components are activated, endocrine system responses favor catabolic actions, nutrients are repartitioned, and less essential functions ∗
Corresponding author. Present address: 214 Greene Hall, Auburn University, Auburn, AL 36849, USA. Tel.: +1-334-844-5515; fax: +1-334-844-5388. E-mail address: [email protected] (J.L. Sartin). 0739-7240/02/$ – see front matter © 2002 Elsevier Science Inc. All rights reserved. PII: S 0 7 3 9 - 7 2 4 0 ( 0 2 ) 0 0 1 7 1 - 6
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such as reproduction and growth are suspended. Although many different types of infectious diseases exist and the specific response to differing diseases may vary, some of the mechanisms by which the animal shifts nutrients from growth and reproduction to immune function are likely consistent across various diseases. In the study of the response to disease, it is often useful to utilize models of the disease process as opposed to the disease itself. One model for disease that is commonly used is the administration of endotoxin or lipopolysaccharide (LPS). The presence of endotoxin, a component of the cell wall of gram negative bacteria, has been implicated in septicemia, a cause of 175,000–200,000 deaths annually in the United States [1,2].
2. Effect of endotoxin on cytokine production The effects of endotoxin have been studied in many domestic animals as well as humans and rodents. Following exposure to endotoxin, there is an increase in circulating concentration of a number of cytokines including tumor necrosis factor (TNF), interleukin-1 (IL-1), and interleukin-6 (IL-6) [3]. These cytokines are involved in numerous responses to endotoxin including fever, hypophagia, and general inflammation. Investigations of induction of cytokine production by endotoxin have been limited in sheep. However, intravenous (IV) bolus endotoxin administration resulted in increased TNF activity in the plasma [4] and an increase in plasma concentration of TNF in the sheep [5,6]. Endotoxin administration also increased IL-1 mRNA expression in the choroid plexus of sheep [7]. Some of these cytokines may mediate the effects of endotoxin to regulate the secretion of pituitary hormones in sheep.
3. Endotoxemia and growth hormone Growth hormone (GH) is involved with regulation of metabolism, either directly as in fat catabolism or indirectly as in protein synthesis via insulin-like growth factor-I (IGF-l). In addition, GH has a role in immune modulation. For example, cells of the immune system synthesize GH after exposure to endotoxin [8]. Moreover, GH has profound effects to improve the response of cattle treated with endotoxin [9]. Thus, effects of GH on metabolism and on immune function suggest a critical regulatory event in the animals’ response to sepsis or endotoxemia. 3.1. Endotoxin inhibition of GH—birds, cattle, rats The endotoxin model for study of GH release has been used in a number of species with varied results. Growth hormone release in response to injection of E. coli endotoxin is reduced in birds, cattle, and rodent models [9,10,11], which is paralleled by changes in IGF-l (rats [12]; cattle [13]). Similar effects to those seen with endotoxin were obtained when using cytokines. For example, TNF inhibited GH releasing hormone (GRH)-stimutated GH release from cultured rat pituitary cells [14,15] and cattle pituitary cells in vitro and in vivo [16,17]. Pituitary cells cultured with IL-1 had an increased release of GH [18] while IL-1 stimulated GH
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release following intracerebroventricular (ICV) injection [19,20] at low but not high doses [19]. IL-1 was also reported to inhibit GH surges by either IV or ICV injection [21]. Moreover, IL-1 receptor antagonist infused ICV followed by IV injection of endotoxin prevented the effects of endotoxin to inhibit GH release, indicating a role for IL-1 in the endotoxin inhibition of GH release [22]. The effects of endotoxin to reduce plasma concentrations of GH in rats were suggested to be via a hypothalamic mechanism because: (1) GH inhibition was reversed by use of somatostatin (SS) antiserum [11]; (2) endotoxin elevated hypothalamic SS content [23]; and (3) IL-1 stimulated SS release from cultured fetal neurons [24]. 3.2. Endotoxin stimulation of GH—sheep, pigs, humans Data for sheep, pigs, and humans [5,25,26] indicate that plasma GH concentrations are increased by endotoxin. In contrast to the GH response, endotoxin inhibits IGF-1 in these species [27,28,29]. However, the mechanism and site of action for these different effects on GH release in these models are not known. The effect of endotoxin to increase plasma GH concentrations in sheep was delayed in time of onset and persisted for more than 8 h (Fig. 1; [5]). Moreover, the effects of endotoxin to release GH in sheep were found to be reproduced in vitro using cultured pituitary cells [5]. The effects of endotoxin on in vitro or in vivo GH release were not influenced by the subsequent treatment with GRH [5]. This led to a hypothesis that the effects of endotoxin occurred at the level of the pituitary (rather than the hypothalamus as seen in rats). Possibilities considered were that endotoxin increased cytokine production outside the pituitary (macrophages) which in turn altered GH release, endotoxin stimulated directly the production of cytokines from the
Fig. 1. Endotoxin stimulated increase in plasma concentrations of growth hormone. Endotoxin was administered IV at 0.4 g/kg BW. N = 5 for control and n = 5 for endotoxin. Treatment effect, P < 0.01; [5].
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pituitary to subsequently alter GH release, or endotoxin had a direct effect on somatotrope to increase GH release [5]. Two different types of experiments were employed to determine the site of action of endotoxin on GH release in sheep. One approach [30] utilized portal vein cannulated sheep to determine whether GH release by endotoxin was a result of increased secretion of GH releasing hormone or reduced secretion of SS. Their data indicated that GRH release was unchanged while SS release was actually increased in the sheep, similar to the effect of endotoxin to increase SS in the rat. However, unlike the rat, these hypothalamic releasing factors were not likely responsible for the effects of endotoxin to increase GH release. Moreover, these data argued in favor of a pituitary site of action or another form of hypothalamic mediation of the endotoxin effect on GH. Clearly this mechanism does not account for the increase in plasma GH in sheep. Finally, Vellucci et al. [31] found that IL-1 injected ICV increased plasma cortisol concentrations and increased temperature but had no effect on plasma GH, suggesting little or no central site of action of low doses of IL-1 in mediating GH release in response to endotoxin. In the second experimental approach, Nash et al. [32] determined that TNF increased GH and interleukin-6 (IL-6) mRNA in cultured sheep pituitary cells. Studies by Fry et al. [33] determined the effects of specific cytokines on GH release from cultured sheep pituitary cells. These data provided evidence that interleukin-2 and interferon-␥ had no effects on GH release in vitro in sheep, though both cytokines inhibit GH release from cultured rat pituitary cells [34,35]. As determined for cattle [36], TNF inhibited GRH-stimulated GH release in cultured sheep pituitary cells but had no effect on basal GH release in the sheep [33]. Messenger RNA levels were not determined in this study, but the data suggest even if synthesis were increased by TNF as was described by Nash et al. [32], secretion of GH from these cultured cells did not increase. In view of the effects of TNF to increase IL-6 mRNA [32], attempts were also made to determine whether human IL-6 had an effect on secretion of GH, but there appeared to be no effects, perhaps due to species differences in the IL-6 molecule [33]. However, IL-1 and IL-l␣ both stimulated GH release and IL- increased GH mRNA production and pituitary GH content [33]. GRH had no effects on IL-1-stimulated GH release while SS inhibited both IL-l␣and IL-l-stimulated release of GH. Moreover, the effects on GH release were determined to be mediated via protein kinase A, Ca2+ dependent mechanisms, and the cyclooxygenase pathway. Interestingly, endotoxin effects on GH release were also found to be mediated via the cyclooxygenase pathway, though whether this was an effect directly on the somatotrope to release GH or an effect on GH release mediated through pituitary cytokine production was not determined [33,37].Current studies have been designed to determine the role of IL-1 and TNF in the regulation of GH. These preliminary studies have found that IV injection of both TNF and IL-1 will increase plasma concentrations of GH. In addition, IV injection of human IL-1 receptor antagonist and human soluble TNF receptor (Amgen Inc., Thousand Oaks, CA) will inhibit the effects of endotoxin on GH release [38]. These studies combined with previous data suggest a role for both IL-1 and TNF in regulating the plasma concentrations of GH. Moreover, the data from these studies indicate an effect of endotoxemia that is in part mediated via cytokines at the level of the pituitary gland. Other factors may also play a role in this process but have not been critically examined in the context of endotoxemia. Cortisol release is stimulated by endotoxin and may play a role
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in models of endotoxin reduced GH release. Moreover, cortisol inhibition of GH is observed in a time frame consistent with endotoxin stimulation of cortisol [39,40]. Cortisol may have a role in GH inhibition by endotoxin in rodent models; but if cortisol participates in the endotoxin effect in sheep, it may blunt the effects of endotoxin on GH release but is not likely a mediator for increased GH release. Another factor may be the prolonged decrease in plasma IGF concentrations producing a reduced negative feedback on GH. However, reduced IGF is present in both endotoxin-stimulated GH (sheep) and in models such as cattle and rats, where plasma GH concentrations are reduced. Also, IGF-l changes are slow to develop and probably do not account for increased GH in the sheep. 4. Endotoxemia and LH secretion Multiple investigators have demonstrated that endotoxin causes a decrease in plasma concentration and pulse frequency of LH in the sheep (Fig. 2; [5,41,42]. Battaglia and co-workers also demonstrated that endotoxin disrupted the estradiol induced LH surge following progesterone withdrawal in intact ewes [43,44]. Indirect and direct evidence suggests that endotoxin suppresses LH secretion at the level of the hypothalamus. In experiments examining hypophyseal portal blood, Battaglia and co-workers observed that endotoxin administered IV decreased pulsatile GnRH [41]. Providing further evidence that endotoxin is acting at the level of the brain to suppress LH secretion, Battaglia and co-workers also observed that endotoxin blocks the initial estradiol signaling to the brain to initiate the LH surge and not surge release [43]. Additionally, in vitro endotoxin stimulated an increase in media accumulation of LH from cultured pituitary cells [5], and both
Fig. 2. Endotoxin suppressed plasma concentration of luteinizing hormone. N = 5 per treatment group. LH was reduced from 1–6 h after endotoxin, P < 0.01. There was a reduction in number of LH pulses, P < 0.05; [5].
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IL-1␣ and IL-1 stimulated an increase in media concentration of LH from cultured pituitary cells, although IL-2, TNF, and interferon-␥ did not effect LH concentration [45]. Cumulatively, these data suggest that endotoxin suppresses LH secretion in vivo at the level of the hypothalamus. However, other data suggest that endotoxin may suppress LH secretion at the level of the pituitary. Endotoxin appeared to uncouple GnRH and LH pulse patterns [41,42]. Furthermore, endotoxin suppressed pituitary responsiveness to exogenous GnRH [2]. These data suggest that endotoxin may also affect LH secretion at the level of the pituitary in addition to the inhibitory actions at the hypothalamus. Endotoxin suppression of LH may occur through activation of the stress induced hypothalamic–pituitary–adrenal axis. Stress is generally considered to be detrimental to reproduction. Administration of endotoxin IV resulted in increased circulating cortisol and ACTH as well as increased hypophyseal portal blood concentrations of corticotropin-releasing hormone (CRH) and arginine vasopressin (AVP) [46], and increased concentrations of AVP in the cerebrospinal fluid and plasma [47]. The increase in hypophyseal portal blood concentrations of CRH and AVP stimulated by endotoxin corresponds temporally with decreased hypophyseal portal blood concentrations of GnRH and circulating LH [48]. Central administration of recombinant human IL-1 also increased body temperature, circulating concentration of cortisol, and expression of c-fos mRNA in the paraventricular nucleus and supracoptic nucleus, and CRH mRNA in the PVN [31]. However, central administration of CRH has been demonstrated
Fig. 3. Schematic illustration of possible mechanisms by which endotoxin may increase growth hormone concentrations in sheep. Solid arrows indicate pathways for endotoxin regulation of GH release that are substantiated by the data. The dotted arrows indicate pathways that may exist but are not primary pathways for GH regulation.
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to stimulate an increase in LH secretion in intact ewes and castrated rams [49,50]. Additionally, central administration of AVP did not affect LH secretion [50]. Thus, it is unlikely that the endotoxin-induced stress response is mediating the suppressive effects of endotoxin on LH in sheep. Endotoxin may be acting through the production of cytokines to inhibit LH secretion. The cytokines could arise from either peripheral monocytes or be produced by the hypothalamus or pituitary in response to endotoxin. Administration of cytokines can mimic some of the effects of endotoxin. Administration of recombinant human TNF to lambs included fever and caused a significant increase in plasma concentrations of cortisol, glucagon, and insulin [51]. Central administration of recombinant human IL-1 increased IL-1 mRNA expression in the PVN and in the cells bordering the third ventricle in sheep [31]. These cytokines could then act directly or through mediators such as prostaglandins to inhibit LH secretion. However, central administration of IL-1 did not affect circulating concentrations of prolactin or GH nor expression of AVP mRNA in the PVN and SON [31]. Evidence suggests that prostaglandins may mediate endotoxin suppression of LH secretion. Administration of the prostaglandin synthesis inhibitor, flurbiprofen, prevented endotoxin suppression of LH and GnRH secretion and stimulation of fever but did not prevent the rise in TNF observed following endotoxin administration [52]. However, the endotoxin reduced pituitary responsiveness to exogenous GnRH was not altered by the prostaglandin inhibitor, flurbiprofen [42]. Thus, although it is clear that endotoxin inhibits LH secretion, the complete mechanism by which endotoxin inhibits LH secretion is not yet clear.
Fig. 4. Schematic illustration of possible mechanisms by which endotoxin may decrease luteinizing hormone concentrations in sheep. Arrows indicate primary pathways for LH regulation by endotoxin.
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5. Summary Although not conclusive, the data suggest that endotoxin stimulates increased plasma concentration of GH in sheep at the level of the pituitary (Fig. 3), perhaps via effects of TNF or IL-1. In contrast, endotoxin suppresses plasma concentration of LH in the sheep at the level of the hypothalamus (Fig. 4), although some data do suggest that the ability of the pituitary to respond to GnRH is reduced.
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