Influence of hypercortisolemia on soluble tumor necrosis factor receptor II and interleukin-1 receptor antagonist responses to endotoxin in human beings

doi:10.1016/S0039-6060(05)80352-6

Surgery

Volume 118, Issue 2, August 1995, Pages 406-411

https://doi.org/10.1016/S0039-6060(05)80352-6 Get rights and content

Background. We have previously reported that the antecedent administration of glucocorticoids altered both the hormonal and proinflammatory cytokine responses to lipopolysaccharide (LPS) when administered to human volunteers. In that study, subjects with vastly exaggerated levels of tumor necrosis factor (TNF) and interleukin (IL)-6 12 and 144 hours after cortisol infusion exhibited hemodynamic and hormonal responses no different from those of untreated subjects after endotoxin. The current study examined levels of the antiinflammatory cytokines interleukin-1 receptor antagonist (IL-1ra) and soluble receptors to tumor necrosis factor (sTNF-R) in the same setting of the previous report.

Methods. Hydrocortisone succinate was infused into healthy volunteers. LPS was then injected immediately or was delayed by 6, 12, or 144 hours (C, C-6, C-12, and C-144, respectively). Subjects receiving LPS alone served as controls. Plasma was analyzed to determine levels of TNF, sTNF-R and IL-1ra by enzyme-linked immunosorbent assay before administration of LPS and at 30-minute intervals after administration of LPS for 6 hours.

Results. Levels of sTNF-R increased after LPS administration in all groups (p<0.05 versus baseline) with a significantly higher level recorded in the subjects having received hydrocortisone 144 hours before (C-144, p<0.05 versus all other groups). TNF levels remained undetectable in association with immediate infusion of LPS (C) and the relatively short delay group (C6). This cytokine peaked 90 minutes after LPS in all other groups, with a significantly higher peak in the C-144 subjects when compared with controls. IL-1ra levels rose in all groups but to a lesser extent in the C group (p<0.05).

Conclusions. These data confirm that glucorticoids influence the production of both sTNF-R and IL-1ra. The potential for an exaggerated response of sTNF-R exists for an extended period of time after exposure to glucocorticoids.

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In this article, we have described the pharmacological influence on the mononuclear phagocyte system (MPS) by immunosuppressants as well as by novel specific immunostimulatory agents—mRNA vaccines. Regarding immunosuppressive agents, there are two main groups, which are called the biological and non-biological diseases modifying anti-rheumatic drugs (DMARDs). The representatives of biological DMARDs are anakinra—interleukin-1 receptor antagonist, baricitinib—Janus kinase (JAK) inhibitor, denosumab—receptor activator of nuclear factor-kappa-Β ligand antibody, secukinumab—IL-17 antibody and abatacept—selective T-lymphocytes co-stimulation modulator. These biological DMARDs are affecting monocytes, macrophages and dendritic cells. Certolizumab pegol—tumor necrosis factor (TNF) blocker has its pharmacological effect on monocytes and macrophages. The non-biological DMARDs representatives: glucocorticoids and methotrexate are affecting monocytes and macrophages, and hydroxychloroquine is acting on dendritic cells and macrophages.
The antigen-presenting cells—dendritic cells as well as macrophages play a key role in the determination of the mechanism of action of mRNA vaccines. The currently approved mRNA vaccines act to increase the protein translation, modulate innate and adaptive immunogenicity. Important future directions of research will be to compare and elucidate the immune pathways activated by recently approved mRNA vaccine to improve current approaches based on these mechanisms.
Relationships among psychosocial factors, biomarkers, preeclampsia, and preterm birth in African American women: A pilot
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For example, pro-inflammatory cytokines such as interleukin-1 beta (IL-1β), IL-6, and tumor necrosis factor-alpha (TNF-α) stimulate the HPA axis and increase the output of cortisol (Kunz-Ebrecht, Mohamed-Ali, Fledman, Kirschbaum, & Steptoe, 2003; Witek-Janusek & Mathews, 2000). Cortisol down-regulates these same pro-inflammatory cytokines (Geiss, Varadi, Steinback, Bauer, & Anton, 1997) and stimulates the production of anti-inflammatory cytokines such as IL-1 receptor antagonist (IL-1ra) and soluble TNF-receptor 2 (sTNF-RII) (Barber et al., 1995; Elenkov & Chrousos, 2002), thereby limiting inflammatory responses. During chronic stress, however, cortisol is less effective at suppressing the immune system and inflammation (Elenkov & Chrousos, 2002; Gennaro & Hennessy, 2003; Ruiz, Fullerton, & Dudley, 2003), in part due to a reduced responsiveness of glucocorticoid receptors on immune cells.
To explore the relationships among psychosocial factors (optimism, uncertainty, social support, coping, psychological distress), biomarkers (cortisol, cytokines), preeclampsia, and preterm birth in African American women.
Forty-nine pregnant African American women completed psychosocial questionnaires and had blood collected for biomarkers between 26 and 36 weeks of gestation. Birth outcomes were obtained from birth records.
Women reporting higher levels of social support had lower levels of pro-inflammatory cytokines (IL-2, IL-5, and IL-6). Surprisingly, compared with low-risk pregnant women, women diagnosed with preeclampsia reported more optimism and less avoidance, and had lower levels of cortisol and IFN-γ. Similarly, compared to women with full-term birth, women with preterm birth reported higher levels of optimism and lower levels of avoidance, and had lower levels of IL-10.
Psychosocial factors influence inflammation and pregnancy outcomes. Close assessment and monitoring of psychosocial factors may contribute to improved pregnancy outcomes.
Differences between murine and human sepsis
2014, Surgical Clinics of North America
Counteraction of early circulatory derangement by administration of low dose steroid treatment at the onset of established endotoxemic shock is not directly mediated by TNF-α and IL-6
2012, Steroids
Once a septic condition is progressing, administration of steroids in the pro-inflammatory phase of septic shock ought to yield maximal effect on the subsequent, devastating inflammatory response. Recently, a retrospective study showed that early initiation of corticosteroid therapy improved survival in septic shock. We aimed to prospectively evaluate effects of early administrated hydrocortisone therapy on physiologic variables in a porcine model of septic shock.
Eight anesthetized pigs were given a continuous infusion of endotoxin during this 6 h prospective, randomized, parallel-grouped placebo-controlled experimental study. At the onset of endotoxemic shock, defined as the moment when the mean pulmonary arterial pressure reached the double baseline value, the pigs were either given a single intravenous dose of hydrocortisone (5 mg kg⁻¹) or the corresponding volume of saline.
Mean arterial pressure and systemic vascular resistance index were significantly higher (both p < 0.05), and heart rate was significantly lower (p < 0.05), in the endotoxin + hydrocortisone group as compared to the endotoxin + saline group. Body temperature and blood hemoglobin levels increased significantly in the endotoxin + saline group (both p < 0.05). Urinary hydrocortisone increased significantly in both groups (p < 0.05). There were no significant differences in the plasma levels of TNF-alpha, IL-6 or nitrite/nitrate between the groups.
Early treatment with hydrocortisone ameliorates some endotoxin mediated circulatory derangements, fever response and microvascular outflow. Our results suggest that these effects are not directly mediated by the pro-inflammatory cytokines TNF-alpha or IL-6, nor by NO.
Propensity score analysis evaluating preoperative glucocorticoid administration in elective colectomy
2012, International Journal of Surgery
Citation Excerpt :
Preoperative GC was not associated with an increase in the rate of total complications, major complications, infectious complication and anastomotic leak. The use of preoperative GCs has been shown to effectively attenuate the physiological inflammation induced by surgery.8 A recent systematic review and meta-analysis demonstrated this benefit by showing a significant decrease in the rate of postoperative morbidity in patients undergoing major abdominal surgery.9
Preoperative glucocorticoid (GC) administration attenuates the physiological response to surgery and improves clinical outcomes. However, GC use is not yet universally implemented. A propensity score analysis was performed to evaluate preoperative GC use in elective colectomy.
A retrospective review of prospectively collected data was conducted for all patients who had undergone elective colectomy within an established Enhanced Recovery After Surgery (ERAS) programme at our institution from January 2006 to 2010. Demographic data, surgery type, glucocorticoid administration and clinical outcomes including complication rates and length of hospital stay (LOS) were investigated. Univariate and propensity score analyses were conducted with statistical significance identified as p ≤ 0.05.
There were 253 patients included in the analysis, of which 146 received preoperative GC. There were significant baseline differences between those who received GC and those who did not in male gender (GC: 56 (38%); non-GC: 58 (54%); p = 0.02) and American Society of Anesthesiologists (ASA) III (GC: 40 (27%); non-GC: 43 (40%); p = 0.04). On univariate analysis, there were no significant differences in the incidence of total complications, major complication, anastomotic leak and infectious complication. On propensity score analysis, preoperative GC administration was found to be independently associated with a reduction in LOS (GC: 5; Non-GC: 6; p = 0.04).
Preoperative GC administration is associated with a reduction in LOS without an increase in postoperative complications.
Pathophysiology of acute respiratory distress syndrome. Glucocorticoid receptor-mediated regulation of inflammation and response to prolonged glucocorticoid treatment
2011, Presse Medicale
Citation Excerpt :
avoidance of rebound inflammation. There is ample evidence [35,87–94] that early removal of glucocorticoid treatment may lead to rebound inflammation and an exaggerated cytokine response to endotoxin [95]. Experimental work has shown that short-term exposure of alveolar macrophages [96] or animals to dexamethasone is followed by enhanced inflammatory cytokine response to endotoxin [97].
Based on molecular mechanisms and physiologic data, a strong association has been established between dysregulated systemic inflammation and progression of ARDS. In ARDS patients, glucocorticoid receptor-mediated down-regulation of systemic inflammation is essential to restore homeostasis, decrease morbidity and improve survival and can be significantly enhanced with prolonged low-to-moderate dose glucocorticoid treatment. A large body of evidence supports a strong association between prolonged glucocorticoid treatment-induced down-regulation of the inflammatory response and improvement in pulmonary and extrapulmonary physiology. The balance of the available data from controlled trials provides consistent strong level of evidence (grade 1B) for improving patient-centered outcomes. The sizable increase in mechanical ventilation-free days (weighted mean difference, 6.58 days; 95% CI, 2.93 –10.23; P < 0.001) and ICU-free days (weighted mean difference, 7.02 days; 95% CI, 3.20–10.85; P < 0.001) by day 28 is superior to any investigated intervention in ARDS. The largest meta-analysis on the subject concluded that treatment was associated with a significant risk reduction (RR = 0.62, 95% CI: 0.43–0.91; P = 0.01) in mortality and that the in-hospital number needed to treat to save one life was 4 (95% CI 2.4–10). The balance of the available data, however, originates from small controlled trials with a moderate degree of heterogeneity and provides weak evidence (grade 2B) for a survival benefit. Treatment decisions involve a tradeoff between benefits and risks, as well as costs. This low cost highly effective therapy is familiar to every physician and has a low risk profile when secondary prevention measures are implemented.

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Supported by grant GM-34695 from the U.S. Public Health Service and by a grant from the Royal Dutch Academy of Arts and Sciences (T.v.d.P).

Presented at the Fifty-sixth Annual Meeting of the Society of University Surgcons, Denver, Colo., Feb. 9–11, 1995.

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Surgery

References (22)

The processing and collaborative assay of a reference endotoxin

J Biol Stand

Tumor necrosis factor is involved in the appearance of interleukin-1 receptor antagonist in endotoxemia

J Infect Dis

Glucocorticoid therapy alters hormonal and cytokine responses to endotoxin in man

J Immunol

Elaboration of interleukin-1 receptor antagonist is not attenuated by glucocorticoids after endotoxemia

Arch Surg

Tumor necrosis factor soluble receptors circulate during experimental and clinical inflammation and can protect against excessive tumor necrosis factor α in vitro and in vivo

Proc Natl Acad Sci USA

Experimental endotoxemia in humans: analysis of cytokine release and coagulation, fibrinolytic and complement pathways

Blood

Persistently elevated soluble tumor necrosis factor receptor and interleukin-1 receptor antagonist levels in critically ill patients

J Am Coll Surg

Elevated levels of shed type II IL-1 receptor in sepsis

J Immunol

Interleukin-1 receptor blockade improves survival and hemodynamic performance in Escherichia coli septic shock, but fails to alter host responses to sublethal endotoxemia

J Clin Invest

Influence of hypercortisolemia on the acute-phase protein response to endotoxin in humans

Surgery

Impact of hypercortisolemia on the metabolic and hormonal responses to endotoxin in man

Surg Forum

Cited by (55)

Effects of Selected Non-biological and Biological Disease-Modifying Anti-rheumatic Drugs, and mRNA Vaccines on Mononuclear Phagocyte System

Relationships among psychosocial factors, biomarkers, preeclampsia, and preterm birth in African American women: A pilot

Differences between murine and human sepsis

Counteraction of early circulatory derangement by administration of low dose steroid treatment at the onset of established endotoxemic shock is not directly mediated by TNF-α and IL-6

Propensity score analysis evaluating preoperative glucocorticoid administration in elective colectomy

Pathophysiology of acute respiratory distress syndrome. Glucocorticoid receptor-mediated regulation of inflammation and response to prolonged glucocorticoid treatment

Influence of hypercortisolemia on soluble tumor necrosis factor receptor II and interleukin-1 receptor antagonist responses to endotoxin in human beings*

J Biol Stand

Tumor necrosis factor is involved in the appearance of interleukin-1 receptor antagonist in endotoxemia

J Infect Dis

Glucocorticoid therapy alters hormonal and cytokine responses to endotoxin in man

J Immunol

Elaboration of interleukin-1 receptor antagonist is not attenuated by glucocorticoids after endotoxemia

Arch Surg

Tumor necrosis factor soluble receptors circulate during experimental and clinical inflammation and can protect against excessive tumor necrosis factor α in vitro and in vivo

Proc Natl Acad Sci USA

Experimental endotoxemia in humans: analysis of cytokine release and coagulation, fibrinolytic and complement pathways

Blood

Persistently elevated soluble tumor necrosis factor receptor and interleukin-1 receptor antagonist levels in critically ill patients

J Am Coll Surg

Elevated levels of shed type II IL-1 receptor in sepsis

J Immunol

Interleukin-1 receptor blockade improves survival and hemodynamic performance in Escherichia coli septic shock, but fails to alter host responses to sublethal endotoxemia

J Clin Invest

Influence of hypercortisolemia on the acute-phase protein response to endotoxin in humans

Surgery

Impact of hypercortisolemia on the metabolic and hormonal responses to endotoxin in man

Surg Forum