The present study was designed to determine whether the glucocorticoid inhibitory feedback mechanism plays a role in the well-known tolerance of the neuroendocrine-immune axis response to repeated endotoxemia. Adult male rats underwent adrenalectomy (ADX) and were implanted with a subcutaneous corticosterone (compound B, CB, 75 mg) pellet, or sham operated and implanted with a placebo pellet. On the morning of day 8 after surgery (experimental day, D1), all rats received an intravenous injection of lipopolysaccharide (LPS) (25 µg/kg body weight) which was repeated daily until D5. Blood was drawn via intravenous indwelling catheters before (sample time zero) as well as 1, 2, 3 and 4 h after LPS treatment on D1, 3 and 5 for measurements of corticotropin (ACTH), CB, tumor necrosis factor-α (TNF-α) and leptin. In sham animals, tolerance to repeated LPS administration was complete by D5 for the corticotrope axis and the immune response. In addition, LPS was found to stimulate leptin secretion on day 1 in intact rats, an effect that also disappeared thereafter. ADX + CB rats showed only a partial tolerance of the corticotrope axis on D5, whereas tolerance of the immune response was similar to that found in sham animals. Interestingly, the acute stimulation of leptin secretion by LPS in ADX + CB rats was qualitatively similar to that of intact controls on D1, but plasma leptin levels were significantly reduced on D3 and 5 compared to controls. Our results demonstrate that the adrenal response tolerance of the hypothalamo-pituitary-adrenal axis to repeated endotoxemia. In addition, our finding that TNF-α secretion follows the same pattern in sham-operated and in adrenalectomized animals suggests that unlike the corticotrope axis, tolerance of the immune response does not depend upon stimulated CB levels. The decrease in circulating levels of leptin following ADX is consistent with the stimulatory effects of glucocorticoids on leptin secretion. However, our finding of an acute stimulation of leptin secretion by LPS in ADX + CB animals demonstrates that this effect of endotoxemia is at least partially glucocorticoid independent.

1.
Keller-Wood ME, Shinsako J, Dallman MF: Inhibition of the adrenocorticotropin and corticosteroid responses to hypoglycemia after prior stress. Endocrinology 1983;113:491–496.
2.
Keller-Wood ME, Shinsako J, Dallman MF: Feedback inhibition of adrenocorticotropin hormone by physiological increases in plasma corticosteroids in conscious dogs. J Clin Invest 1983;71:859–866.
3.
Vernikos J, Dallman MF, Bonner C, Katzen A, Shinsako J: Pituitary-adrenal function in rats chronically exposed to cold. Endocrinology 1982;110:413–420.
4.
Kant GJ, Eggleston T, Landman-Roberts L, Kenion CC, Driver GC, Meyerhoff JL: Habituation to repeated stress is stressor specific. Pharmacol Biochem Behav 1985;22:631–634.
5.
Orio MD, Brodish A: Effects of chronic stress on in vivo pituitary-adrenocortical responses to corticotropin releasing hormone. Neuropeptides 1990;15:143–452.
6.
Naito Y, Fukata J, Nakai Y, Hirai Y, Tamai S, Mori K, Imura H: Chronic effects of interleukin-1 on hypothalamus pituitary and adrenal glands in rats. Neuroendocrinology 1990;51:637–641.
7.
Sweep CGJ, Van der Meer MJM, Hermus ADRMM, Smals AGH, Van der Meer JWM, Pesman GJ, Wilmensen SJ, Benraad TJ, Klopenborg PWC: Chronic stimulation of pituitary adrenal axis in rats by interleukin-1 infusion: In vivo and in vitro studies. Endocrinology 1992;130:1153–1164.
8.
Mengozzi M, Ghezzi P: Defective tolerance to toxic and metabolic effect of interleukin-1. Endocrinology 1991;128:1668–1672.
9.
Zuckerman SH, Shellhaas J, Buller LD: Differential regulation of lipopolysaccharide-induced interleukin 1 and tumor necrosis factor synthesis: Effects of endogenous and exogenous glucocorticoids and the role of the pituitary-adrenal axis. Eur J Immunol 1989;19:301–305.
10.
Evans GF, Zuckerman SH: Glucocorticoid-dependent and independent mechanisms involved in lipopolysaccharide tolerance. Eur J Immunol 1991;21:1973–1979.
11.
Weidenfeld J, Abramsky O, Ovadia H: Effect of interleukin-1 on ACTH and corticosterone secretion in dexamethasone and adrenalectomized pretreated male rats. Neuroendocrinology 1990;50:650–654.
12.
Plata-Salaman CR, Borkoski JP: Chemokines/intercrines and central regulation of feeding. Am J Physiol 1994;266:R1711–R1715.
13.
Fantino M, Wieteska L: Evidence for a direct central anorectic effect of tumor-necrosis-factor-alpha in the rat. Physiol Behav 1993;53:477–483.
14.
Grunfeld C, Zhao C, Fuller J, Pollack A, Moser A, Friedman J, Feingold K: Endotoxin and cytokines induce expression of leptin, the ob gene product, in hamsters. J Clin Invest 1996;97:2152–2157.
15.
Ahima RS, Prabakaran D, Mantzoros C, Qu D, Lowell B, Maratos-Flier E, Flier JS: Role of leptin in the neuroendocrine response to fasting. Nature 1996;382:250–252.
16.
Spinedi E, Giacomini M, Jacquier MC, Gaillard RC: Change in the hypothalamo-corticotrope axis after bilateral adrenalectomy: Evidence for a median eminence site of glucocorticoids action. Neuroendocrinology 1991;53:160–170.
17.
Akana SF, Cascio CS, Shinsako J, Dallman MF: Corticosterone: Narrow range required for normal body and thymus weight and ACTH. Am J Physiol 1985;249:R527–R532.
18.
Hauger RL, Thrivikraman KV, Plotsky PM: Age-related alterations of hypothalamo-pituitary-adrenal axis function in male Fisher 344 rats. Endocrinology 1994;134:1528–1536.
19.
Zar JH: Biostatistical Analysis. Englewood Cliffs, Prentice-Hall, 1974.
20.
Ziegler-Heitbrock HW: Molecular mechanism in tolerance to lipopolysaccharide. J Inflamm 1995;45:13–26.
21.
Besson PB: Tolerance to bacterial pyrogens. I. Factors influencing its development. J Exp Med 1947;86:29–44.
22.
Wang MH, Flad HD, Feist W, Brade H, Kusumoto S, Rietschel ET, Imer AJ: Inhibition of endotoxin-induced interleukin-6 production by synthetic lipid A partial structures in human peripheral blood mononuclear cells. Infect Immun 1991;59:4655–4664.
23.
Warren HS, Knights CV, Siber GR: Neutralization and lipoprotein binding of lipopolysaccharides in tolerant rabbit serum. J Infect Dis 1986;154:784–791.
24.
Greisman SE, Young EJ, Carrozza FA: Mechanism of endotoxin tolerance. V. Specificity of the early and late phases of pyrogenic tolerance. J Immunol 1969;103:1223–1236.
25.
Seckinger P, Zhang JH, Hauptmann B, Dayer JM: Characterization of a tumor necrosis factor alpha (TNF alpha) inhibitor: Evidence of immunological cross-reactivity with TNF receptor. Proc Natl Acad Sci USA 1990;84:5188–5192.
26.
Hannum CH, Wicox CJ, Arend WP, Joslin FG, Dripps KJ, Heimdal PL, Armes LG, Sommer A, Eisenberg SP, Thompson RC: Interleukin-1 receptor antagonist activity of a human interleukin-1 inhibitor. Nature 1990;343:336–340.
27.
Szabo C, Thiermann C, Wu CC, Perretti M, Vane JR: Attenuation of the induction of nitric oxide synthase by endogenous glucocorticoids accounts for endotoxin tolerance in vivo. Proc Natl Acad Sci USA 1994;91:271–275.
28.
Harbuz MS, Lightman SL: Stress and the hypothalamo-pituitary-adrenal axis: Acute, chronic and immunological activation. J Endocrinol 1992;134:327–339.
29.
Dallman MF, Jones MT: Corticosteroid feedback control of ACTH secretion: Effects of stress induced corticosterone secretion on subsequent stress responses in the rat. Endocrinology 1973;92:1367–1375.
30.
Akana SF, Jacobson L, Cascio CS, Shinsako J, Dallman MF: Constant corticosterone replacement normalizes basal adrenocorticotropin (ACTH) but permits sustained ACTH hypersecretion after stress in adrenalectomized rats. Endocrinology 1988;122:1337–1342.
31.
Akana SF, Cascio CS, Dallman MF: Reset in the adrenocortical system: ACTH sensitivity to corticosterone changes between morning and evening. Endocrinology 1986;119:2325–2332.
32.
Besedovsky H, Del Rey A, Sorkin E, Dinarello CA: Immunoregulatory feedback between interleukin-1 and glucocorticoid hormones. Science 1986;233:652–654.
33.
Hadid R, Spinedi E, Giovambattista A, Chautard T, Gaillard RC: Decreased hypothalamo-pituitary-adrenal axis response to neuroendocrine challenge under repeated endotoxemia. Neuroimmunomodulation 1996;3:62–68.
34.
Hadid R, Spinedi E, Daneva T, Grau G, Gaillard RC: Repeated endotoxin treatment decreases immune and hypothalamo-pituitary-adrenal axis response: Effects of orchidectomy and testosterone therapy. Neuroendocrinology 1995;62:348–355.
35.
Sharp BM, Matta SG, Peterson PK, Newton R, Chao C, McAllen K: Tumor necrosis factor alpha is a potent ACTH secretagogue: Comparison to interleukin-1 beta. Endocrinology 1989;124:3131–3133.
36.
Spinedi E, Hadid R, Daneva T, Gaillard RC: Cytokines stimulate the CRH but not the vasopressin neuronal system: Evidence for a median eminence site of interleukin-6 action. Neuroendocrinology 1992;56:46–53.
37.
Mekaouche M, Siaud P, Givalois L, Barbanel G, Malaval F, Maurel D, Assenmacher I, Ixart G: Different responses of plasma ACTH and corticosterone and of plasma interleukin-1β to single and recurrent endotoxin challenges. J Leukocyte Biol 1996;59:341–346.
38.
Madej T, Boguski MS, Bryant H: Threading analysis suggests that the obese gene product may be a helical cytokine. FEBS Lett 1995;373:13–18.
39.
Rock FL, Altmann SW, van Heek M, Kastelein RA, Bazan JF: The leptin haemopoietic cytokine fold is stabilized by an intrachain disulfide bond. Horm Metab Res 1996;28:649–652.
40.
Tartaglia LA, Dembski M, Weng X, Deng N, Culpepper J, Devos R, Richards GJ, Campfield LA, Clark FT, Deeds J, Muir C, Sanker S, Moriarty A, Moore KJ, Smutko JS, Mays GG, Woolf EA, Monroe CA, Tepper RI: Identification and expression cloning of a leptin receptor, OB-R. Cell 1995;83:1263–1271.
41.
De Vos P, Saladin R, Auwerx J, Staels B: Induction of Ob gene expression by corticosteroids is accompanied by body weight loss and reduced food intake. J Biol Chem 1995;270:15958–15961.
42.
Murakami T, Iida M, Shima K: Dexamethasone regulates obese expression in isolated rat adipocytes. Biochem Biophys Res Comm 1995;214:1260–1267.
43.
Spinedi E, Gaillard RC: A regulatory loop between the hypothalamo-pituitary-adrenal (HPA) axis and circulating leptin: A physiological role of ACTH. Endocrinology 1998;139:4016–4020.
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