Jozef Rovensky

Low- versus High-Baseline Epinephrine Output Shapes Opposite Innate Cytokine Profiles: Presence of Lewis- and Fischer-Like Neurohormonal Immune Phenotypes in Humans?

Immunogenetic mechanisms operating within the immune system are known to influence cytokine profiles and disease susceptibility. Yet the role of the individual’s neurohormonal background in these processes remains undefined. Hormonal imbalances are documented in immune-related diseases, but it is unclear whether this represents a secondary phenomenon or a primary “defect” related to specific neurohormonal immune phenotype(s). We report that in a large subpopulation of healthy humans the baseline epinephrine output (but not cortisol and sex steroid hormones) correlated inversely with proinflammatory and positively with anti-inflammatory cytokine production. Thus, low vs high epinephrine excretors had a 2- to 5-fold higher TNF-α and IL-12 production but 2-fold lower IL-10 production induced by LPS ex vivo. In alternative settings, we found low baseline levels and profoundly blunted stress-induced epinephrine responses but high TNF-α levels in Lewis vs Fischer inbred rats. Additionally, isoproterenol, a β adrenoreceptor agonist suppressed LPS-induced TNF-α production, with more pronounced effect in Lewis than in Fischer rats. In human monocytes, epinephrine and the β2 adrenoreceptor agonist fenoterol potently inhibited LPS-induced TNF-α and IL-12, but stimulated IL-10 production. The order of potency for hormones able to inhibit IL-12 production ex vivo was: epinephrine > norepinephrine > = 1,25-(OH)2 vitamin D3 > hydrocortisone. This indicates that baseline epinephrine conditions cytokine responsiveness and through this mechanism intrinsic hypo- or hyperactive adrenal medullas in some individuals may shape opposite cytokine profiles. Since Lewis and Fischer rats have opposite susceptibility to experimental immunological diseases, this suggests that the parallel human phenotypes could be linked to differing responsiveness and susceptibility to infections and immune/inflammatory-related conditions.

An endocrinologist's view on relative adrenocortical insufficiency in rheumatoid arthritis

The concept of relative adrenal insufficiency (RAI) has been originally introduced to describe a situation in which critically ill patients, without any prior risk or evidence for adrenal insufficiency, have total serum cortisol levels inadequate for the severity of patients’ illness. The concept provided a framework for other disease states, in which higher than normal adrenal function could be expected, such as in chronic inflammation. An intense research in RAI field highlighted some new methodological aspects that significantly improved assessment of adrenal function in chronic illness. Measurement of salivary cortisol may provide additional information on locally available cortisol in target tissues. Low levels of dehydroepiandrosterone (DHEAS) for given age and gender were confirmed as a simple and reliable indicator of decreased adrenal function, even in subjects with normal baseline cortisol or normal corticotropin‐stimulated cortisol response. Combined lower DHEAS and lower baseline cortisol levels could be an example of hypocompetence of adrenocortical function, yet clinically not apparent.

An endocrinologist's view on relative adrenocortical insufficiency in rheumatoid arthritis: Annals of the New York Academy of Sciences

The concept of relative adrenal insufficiency (RAI) has been originally introduced to describe a situation in which critically ill patients, without any prior risk or evidence for adrenal insufficiency, have total serum cortisol levels inadequate for the severity of patients’ illness. The concept provided a framework for other disease states, in which higher than normal adrenal function could be expected, such as in chronic inflammation. An intense research in RAI field highlighted some new methodological aspects that significantly improved assessment of adrenal function in chronic illness. Measurement of salivary cortisol may provide additional information on locally available cortisol in target tissues. Low levels of dehydroepiandrosterone (DHEAS) for given age and gender were confirmed as a simple and reliable indicator of decreased adrenal function, even in subjects with normal baseline cortisol or normal corticotropin‐stimulated cortisol response. Combined lower DHEAS and lower baseline cortisol levels could be an example of hypocompetence of adrenocortical function, yet clinically not apparent.

Increased production of IL-6 and IL-17 in lipopolysaccharide-stimulated peripheral mononuclears from patients with rheumatoid arthritis.

TLR4-mediated inflammatory responses are important for innate immune functions, thus their alterations may participate in the pathogenesis of rheumatoid arthritis (RA). Cortisol is one of the most potent immunomodulatory hormones involved in control of inflammation. In this study, we analyzed TLR4-mediated responses and cortisol effects on the process in peripheral blood mononuclear cells (PBMC) from RA patients. Lipopolysaccharide-stimulated PBMC from 23 female patients and 15 healthy controls were cultured in the presence or absence of cortisol (1 μM) for 24 h. A panel of 17 inflammatory cytokines was analyzed in the cell culture supernatants. Higher (p < 0.05) concentrations of IL-6, IL-17 and MCP-1 were found in lipopolysaccharide-stimulated PBMC from RA patients compared to controls. After normalization of stimulated cytokine secretion to unstimulated cells, a significantly higher (p < 0.05) IL-6 and G-CSF production was found in RA PBMC. Cortisol induced stronger (p < 0.05) suppression of lipopolysaccharide-stimulated secretion of IL-1β, IL-6, IL-17 and G-CSF in RA group compared to controls. The observed higher production of the key inflammatory cytokines by RA PBMC to lipopolysaccharide stimulation supports involvement of TLR4-mediated processes in RA pathogenesis. The higher sensitivity of LPS-stimulated RA PBMC to immunosuppressive effects of cortisol may reflect adaptive processes to chronic inflammation.

Autonomic Nervous System Function in Rheumatoid Arthritis

The sympathoneural and the adrenomedullary systems are involved in regulation of immune processes. Their impairment has been suggested in patients with rheumatoid arthritis (RA). In this study, sympathetic response to orthostasis was evaluated in 22 RA females with <40xa0years of age and in 15 matched healthy controls. The testing consisted of stabilization period in supine position, legs-up position, 10xa0min of orthostasis and again supine position. In each of the body position blood samples were drawn, blood pressure and electrocardiogram was recorded. Plasma levels of epinephrine (EPI) and norepinephrine (NE) were measured and sympathoneural activity was evaluated by analysis of heart rate variability (HRV). During the testing, RA patients had similar EPI and NE concentrations compared to controls. Baseline diastolic blood pressure tended to be higher in RA patients compared to controls; however, blood pressure response to orthostasis was comparable between the groups. The RA and control groups did not differ in heart rate and HRV parameters. This study showed normal reactivity of the sympathoneural and the adrenomedullary systems during orthostatic challenge in RA patients younger than 40xa0years.

Adrenocortical Response to Low‐dose ACTH Test in Female Patients with Rheumatoid Arthritis

Alterations in adrenal steroid production have been suggested in females with rheumatoid arthritis (RA). The aim of the present study was to assess adrenocortical function in RA females. We examined 11 female RA patients (RA: age 30 ± 2 years, BMI 21.0 ± 0.7 kg/m2) and 10 matched healthy controls (C: age 31 ± 1 years, BMI 21.6 ± 0.6 kg/m2). Low‐dose adrenocorticotropic hormone (ACTH) test (i.v. bolus of 1 μg synthetic ACTH) was performed at 10.00 h with blood sampling every 15 min for 90 min. Cortisol, 17‐OH‐progesterone (17OHP), androstenedione (ASD), and dehydroepiandrosterone (DHEA) were assayed in plasma. Baseline cortisol levels were higher in RA patients (RA: 385 ± 38 versus C: 229 ± 28 nmol/L, P= 0.007). In both study groups, ACTH administration increased all the four steroids measured (P < 0.001). Cortisol response to ACTH administration was diminished in RA patients when compared to controls (Δmax: 284 ± 24 in RA versus 424 ± 31 nmol/L in C, P= 0.002). ACTH‐induced maximal rise in plasma DHEA was significantly lower in RA patients when compared to controls (Δmax: 2.59 ± 0.68 in RA versus 5.57 ± 1.25 ng/mL in C, P= 0.015). No significant between‐groups differences were found in responses of ASD or 17OHP. The molar ratio of ASD:cortisol was significantly lower (P < 0.05) in RA patients at base line, but did not differ during ACTH test. After ACTH bolus, the cortisol:17OHP ratio decreased significantly in the RA group (P < 0.001), whereas there was no change in the control group. The present results show decreased secretion of cortisol and DHEA in RA patients in response to ACTH, suggesting a subtle HPA hypofunction at the adrenocortical level.