Repeated Endotoxin Treatment Decreases Immune and Hypothalamo-Pituitary-Adrenal Axis Responses: Effects of Orchidectomy and Testosterone Therapy

Hadid, Rafi; Spinedi, Eduardo; Daneva, Tatiana; Grau, Georges E.; Gaillard, Rolf C.

doi:10.1159/000127024

Cited by 33 publications

(29 citation statements)

References 22 publications

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“…We recently found that repeated injections of LPS in intact mice over a 5-days period induce tolerance of both the immune (TNF-α) and the neuroendocrine (corticotrope) axes [33, 34]. In the present study, corticotrope hyperresponsiveness appears in ADX + CB animals, whereas tolerance of TNF-α secretion to repeated LPS injections remains normal.…”

Section: Discussionsupporting

confidence: 54%

Role of Glucocorticoids in the Response of the Hypothalamo-Corticotrope, Immune and Adipose Systems to Repeated Endotoxin Administration

et al. 1999

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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.

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Section: Discussionsupporting

confidence: 54%

Role of Glucocorticoids in the Response of the Hypothalamo-Corticotrope, Immune and Adipose Systems to Repeated Endotoxin Administration

et al. 1999

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“…The different adrenal response to acute or chronic LPS administration can be explained by a tolerance phenomenon. Different data have been reported depending on the times of administration and the doses used -from a lowered to an almost absent adrenal response to LPS (Mefford et al 1991, Mengozzi & Ghezzi 1991, Hadid et al 1995. The tolerance to chronic LPS administration seems to be related to decreased macrophage responsiveness to LPS, rather than to a decreased neuroendocrine response to cytokines (Mefford et al 1991, Hadid et al 1996.…”

Section: Discussionmentioning

confidence: 98%

Effects of endotoxin lipopolysaccharide administration on the somatotropic axis

Soto¹,

Martin²,

Millán³

et al. 1998

Journal of Endocrinology

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The aim of this work was to study the effect of chronic activation of the immune system on the somatotropic axis. Accordingly, the changes in growth hormone (GH) secretion, circulating insulin-like growth factor-I (IGF-I) and IGF binding proteins (IGFBPs) in response to endotoxin lipopolysaccharide (LPS) administration were examined in adult male Wistar rats. Acute LPS injection (2·5, 25 or 250 µg/kg) increased serum corticosterone in a dosedependent manner and decreased serum levels of insulin and IGF-I, serum GH concentration declined linearly as the LPS dose increased. Western ligand blot showed an increase in the 33 kDa band (corresponding to IGFBP-1 and IGFBP-2) in the rats that received the highest dose of LPS (250 µg/kg). Chronic LPS administration (250 µg/kg daily for 8 days) significantly decreased body weight, serum levels of IGF-I and pituitary GH content, whereas it increased circulating IGFBP-3 (47 kDa band), IGFBP-1 and IGFBP-2 (33 kDa band) and the 24 kDa band (which possibly corresponds to IGFBP-4). Serum concentration of corticosterone and hypothalamic somatostatin content were also increased by chronic LPS treatment. These data suggest that the decrease in GH and IGF-I secretion and the increase in circulating IGFBPs are important mechanisms in body weight loss during chronic inflammation.

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“…64 Plasma IL-1 and TNF-a responses to repeated LPS injections were much smaller than those to acute LPS injection. 64,77 The decreased cytokine production may be due to an alteration in peripheral sympathetic tone, 79,80 but it remains unclear whether repeated LPS injection altered cytokine receptor or neuronal responses at the post-receptor level. A normal glucocorticoid response to endotoxemia seems to be necessary for the development of full tolerance of the HPA axis.…”

Section: Repeated Lps Administrationmentioning

confidence: 99%

Review: Endotoxin and the hypothalamo-pituitary-adrenal (HPA) axis

Beishuizen

Thijs

2003

Journal of Endotoxin Research

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Endotoxin is considered to be a systemic (immunological) stressor eliciting a prolonged activation of the hypothalamo-pituitary-adrenal (HPA) axis. The HPA-axis response after an endotoxin challenge is mainly due to released cytokines (IL-1, IL-6 and TNF-a) from stimulated peripheral immune cells, which in turn stimulate different levels of the HPA axis. Controversy exists regarding the main locus of action of endotoxin on glucocorticoid secretion, since the effect of endotoxin on this neuro-endocrine axis has been observed in intact animals and after ablation of the hypothalamus; however, a lack of LPS effect has been described at both pituitary and adrenocortical levels. The resulting increase in adrenal glucocorticoids has well-documented inhibitory effects on the inflammatory process and on inflammatory cytokine release. Therefore, immune activation of the adrenal gland by endotoxin is thought to occur by cytokine stimulation of corticosteroidreleasing hormone (CRH) production in the median eminence of the hypothalamus, which, in turn stimulates the secretion of ACTH from the pituitary. Acute administration of endotoxin stimulates ACTH and cortisol secretion and the release of CRH and vasopressin (AVP) in the hypophysial portal blood. During repeated endotoxemia, tolerance of both immune and HPA function develops, with a crucial role for glucocorticoids in the modulation of the HPA axis. A single exposure to a high dose of LPS can induce a long-lasting state of tolerance to a second exposure of LPS, affecting the response of plasma TNF-a and HPA hormones. Although there are gender differences in the HPA response to endotoxin and IL-1, these responses are enhanced by castration and attenuated by androgen and estrogen replacement. Estrogens attenuate the endotoxin-induced stimulation of IL-6, TNF-a and IL-1ra release and subsequent activation in postmenopausal women. There appears to be a temporal and functional relation between the HPA-axis response to endotoxin and nitric oxide formation in the neuro-endocrine hypothalamus, suggesting a stimulatory role for nitric oxide in modulating the HPA response to immune challenges. demonstrate higher plasma levels of IL-1 and TNF-a. Elevation of plasma glucocorticoids results in suppression of cytokines such as IL-1, IL-6, and TNF-a and in up-regulation of other cytokines, such as IL-4 and IL-10, and cytokine receptors. Thus, by regulation of cytokine production and action, the HPA axis contributes to modulation of the response to inflammation/infection. In addition, the role of HPA activation has been suggested to be a negative feedback system provided by the immunosuppressive activity of glucocorticoids, limiting inflammatory responses and preventing the immune system from over-reacting and causing tissue damage or autoimmunity.As early as 1957, Wexler et al. suggested that LPS could induce ACTH release since they found a depletion of ascorbic acid and cholesterol in the adrenal glands. 10 Moreover, LPS was not able to cause these changes in hypophysectomized rats. ...

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Repeated Endotoxin Treatment Decreases Immune and Hypothalamo-Pituitary-Adrenal Axis Responses: Effects of Orchidectomy and Testosterone Therapy

Cited by 33 publications

References 22 publications

Role of Glucocorticoids in the Response of the Hypothalamo-Corticotrope, Immune and Adipose Systems to Repeated Endotoxin Administration

Role of Glucocorticoids in the Response of the Hypothalamo-Corticotrope, Immune and Adipose Systems to Repeated Endotoxin Administration

Effects of endotoxin lipopolysaccharide administration on the somatotropic axis

Review: Endotoxin and the hypothalamo-pituitary-adrenal (HPA) axis

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