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

Abstract

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. ...

Integrated Inflammatory Stress (ITIS) Model

“…The interaction between the systems is that cytokines activates the HPA axis, while the hormone cortisol has an anti-inflammatory effect endotoxins (e.g., lipopolysaccharides, LPS) which is found in the outer membrane of gram-negative bacteria and known to activate the immune response (Amersfoort et al 2003;Vedder et al 1999). It is of importance that the inflammation is tightly regulated, since a too extensive response can cause further tissue damage and chronic inflammation, while an insufficient response can lead to serious infections and sepsis (Beishuizen and Thijs 2003;Sternberg 2006). Necessary components of the response regulation are cytokines, which can be classified into two principal groups: pro-inflammatory cytokines, such as interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-α), and anti-inflammatory cytokines, such as interleukin-10 (IL-10) and transforming growth factor beta (TGF-β) (Beishuizen and Thijs 2003;Tracey 2002).…”

“…It is of importance that the inflammation is tightly regulated, since a too extensive response can cause further tissue damage and chronic inflammation, while an insufficient response can lead to serious infections and sepsis (Beishuizen and Thijs 2003;Sternberg 2006). Necessary components of the response regulation are cytokines, which can be classified into two principal groups: pro-inflammatory cytokines, such as interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-α), and anti-inflammatory cytokines, such as interleukin-10 (IL-10) and transforming growth factor beta (TGF-β) (Beishuizen and Thijs 2003;Tracey 2002). Pro-inflammatory cytokines promote inflammation, while anti-inflammatory cytokines inhibit the response to an infection.…”

“…The secreted ACTH is moved by the bloodstream to the adrenal among others, where it affects the adrenal to release cortisol. Cortisol feeds back on hypothalamus and inhibits the release of CRH and ACTH, leading to a down-regulation of the cortisol synthesis (Beishuizen and Thijs 2003;Walker et al 2012;Webster and Sternberg 2004). The secretion of cortisol has been studied extensively revealing both circadian and ultradian oscillations in the concentration (Rankin et al 2012).…”

“…1. Cortisol has anti-inflammatory effects, and cytokines are believed to activate the HPA axis (Beishuizen and Thijs 2003;Sternberg 2006;Tracey 2002;Webster and Sternberg 2004;Yeager et al 2009). Models of the interaction between these two subsystems will increase the understanding of the inflammatory response and lead to refined treatments of immune system disorders such as rheumatoid arthritis, Crohn's disease, atherosclerosis, diabetes and Alzheimer's disease.…”

“…The secretion of CRH results in a secretion of ACTH leading to a secretion of cortisol which in turn inhibits further up-regulation of CRH and ACTH (Beishuizen and Thijs 2003;Sternberg 2006). When an endotoxin challenge is introduced to the system, the phagocytic cells are activated to eliminate the threat (Amersfoort et al 2003;Tracey 2002).…”