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Biomedical subjects

Rainer H Straub

Publications and source records attributed to Rainer H Straub.

At least 19 recordsLinked to original sources
PubMed2006

Anti-interleukin-6 receptor antibody therapy favors adrenal androgen secretion in patients with rheumatoid arthritis: a randomized, double-blind, placebo-controlled study.

OBJECTIVE: Proinflammatory cytokines such as tumor necrosis factor (TNF) were demonstrated to inhibit adrenal steroidogenesis in patients with rheumatoid arthritis (RA), and this was particularly evident in the increase in adrenal androgen levels during anti-TNF therapy. This study investigated the influence on steroidogenesis of an interleukin-6 (IL-6)-neutralizing strategy using IL-6 receptor monoclonal antibodies (referred to as MRA). METHODS: In a placebo-controlled, double-blind, randomized study over 12 weeks in 29 patients with RA being treated with prednisolone, 13 of whom received placebo and 16 of whom received 8 mg MRA/kg body weight, the effects of MRA on serum levels of adrenocorticotropic hormone (ACTH), cortisol, 17-hydroxyprogesterone (17OHP), dehydroepiandrosterone (DHEA), DHEA sulfate (DHEAS), androstenedione (ASD), estrone, and 17beta-estradiol, as well as their respective molar ratios, were determined. RESULTS: MRA therapy markedly improved clinical signs of inflammation (the erythrocyte sedimentation rate, swollen joint score, and Disease Activity Score in 28 joints). Serum levels of ACTH and cortisol and the molar ratio of cortisol to ACTH did not change. Although serum levels of DHEA and DHEAS remained stable during therapy, the DHEAS:DHEA molar ratio significantly decreased in treated patients (P = 0.048). Serum levels of ASD as well as the ASD:cortisol and ASD:17OHP molar ratios increased in MRA-treated patients (minimum P < 0.004). Serum levels of estrone and 17beta-estradiol did not change. but the estrone:ASD molar ratio (an indicator of aromatization) decreased during 12 weeks of MRA treatment (P = 0.001). CONCLUSION: Neutralization of IL-6 increases secretion of biologically active adrenal androgens in relation to that of precursor hormones and estrogens. This is another important indication that proinflammatory cytokines interfere with adrenal androgen steroidogenesis in patients with RA.

17-alpha-Hydroxyprogesterone↗
PubMed2006

Steroid hormones strongly support bovine articular cartilage integration in the absence of interleukin-1beta.

OBJECTIVE: Posttraumatic integration of articular cartilage at fracture sites is essential for mechanical stability of cartilage, and ruptured cartilage is a prerequisite for early osteoarthritis. This study was undertaken to investigate effects on articular cartilage integration mediated by steroid hormones, interleukin-1beta (IL-1beta), and combinations thereof. METHODS: Articular cartilage blocks were cultured in partial apposition for 2 weeks with ascorbic acid, testosterone, 17beta-estradiol, and dehydroepiandrosterone (DHEA), with or without IL-1beta. Mechanical integration was measured as adhesive strength, i.e., the maximum force at rupture of integrated cartilage blocks divided by the overlap area. Glycosaminoglycan content was used to study synthesized extracellular matrix. RESULTS: Culture in medium without supplements did not lead to integration (adhesive strength 0 kPa). With administration of ascorbic acid (100 microg/ml), the median adhesive strength was 49 kPa. In comparison with ascorbic acid alone, all steroid hormones induced a strong, concentration-dependent stimulation of integration (with maximum values observed with DHEA at 3 x 10(-5)M, testosterone at 10(-8)M, and 17beta-estradiol at 10(-11)M). For testosterone and 17beta-estradiol, this was also reflected by an increase of glycosaminoglycan content. Adhesive strength was increased with IL-1beta at 10 pg/ml, but not at 1 pg/ml or 100 pg/ml. In the presence of both IL-1beta and sex hormones, integration of articular cartilage was reduced. CONCLUSION: This is the first study to demonstrate that steroid hormones such as 17beta-estradiol, DHEA, and testosterone stimulate articular cartilage integration. This effect is abrogated by low concentrations of IL-1beta. In the absence of IL-1beta or after neutralization of IL-1beta, steroid hormones might be favorable adjuvant compounds to optimize cartilage integration.

Animals↗
PubMed2006

Failure of catecholamines to shift T-cell cytokine responses toward a Th2 profile in patients with rheumatoid arthritis.

To further understand the role of neuro-immunological interactions in the pathogenesis of rheumatoid arthritis (RA), we studied the influence of sympathetic neurotransmitters on cytokine production of T cells in patients with RA. T cells were isolated from peripheral blood of RA patients or healthy donors (HDs), and stimulated via CD3 and CD28. Co-incubation was carried out with epinephrine or norepinephrine in concentrations ranging from 10(-5) M to 10(-11) M. Interferon (IFN)-gamma, tumour necrosis factor (TNF)-alpha, interleukin (IL)-4, and IL-10 were determined in the culture supernatant with enzyme-linked immunosorbent assay. In addition, IFN-gamma and IL-10 were evaluated with intracellular cytokine staining. Furthermore, basal and agonist-induced cAMP levels and catecholamine-induced apoptosis of T cells were measured. Catecholamines inhibited the synthesis of IFN-gamma, TNF-alpha, and IL-10 at a concentration of 10(-5) M. In addition, IFN-gamma release was suppressed by 10(-7) M epinephrine. Lower catecholamine concentrations exerted no significant effect. A reduced IL-4 production upon co-incubation with 10(-5) M epinephrine was observed in RA patients only. The inhibitory effect of catecholamines on IFN-gamma production was lower in RA patients as compared with HDs. In RA patients, a catecholamine-induced shift toward a Th2 (type 2) polarised cytokine profile was abrogated. Evaluation of intracellular cytokines revealed that CD8-positive T cells were accountable for the impaired catecholaminergic control of IFN-gamma production. The highly significant negative correlation between age and catecholamine effects in HDs was not found in RA patients. Basal and stimulated cAMP levels in T-cell subsets and catecholamine-induced apoptosis did not differ between RA patients and HDs. RA patients demonstrate an impaired inhibitory effect of catecholamines on IFN-gamma production together with a failure to induce a shift of T-cell cytokine responses toward a Th2-like profile. Such an unfavorable situation is a perpetuating factor for inflammation.

Adult↗
PubMed2006

Effects of testosterone, 17beta-estradiol, and downstream estrogens on cytokine secretion from human leukocytes in the presence and absence of cortisol.

Estrogens at physiological concentrations are thought to play an immune-stimulating role, whereas androgens have an anti-inflammatory impact. However, their role on cytokine secretion in the presence or absence of cortisol has not been investigated. Furthermore, the role of hydroxylated estrogens downstream of 17beta-estradiol (E2) on secretion of tumor necrosis factor (TNF) is not known. In this study on peripheral blood leukocytes of healthy male subjects, we scrutinized the influence of prior sex hormones (for 24 h) with and without later addition of cortisol (for another 24 h) on stimulated secretion of TNF, IL-2, IL-4, IL-6, IL-10, and interferon-gamma (IFN-gamma). E2 stabilized or increased immune stimuli-induced secretion of TNF, IL-2, IL-4, IL-6, IL-10, and IFNgamma in relation to testosterone. Testosterone, in contrast, inhibited (IL-2, IL-4, IL-10) or tended to inhibit stimulated secretion of these cytokines (TNF, IFNgamma). This effect of E2 was pronounced at a concentration of 10(-10) M (testosterone: 10(-7) M) in the presence of cortisol. E2 (10(-8) M, 10(-10) M) and testosterone (10(-7) M) did not change glucocorticoid receptor expression. The downstream estrogens 2OH-estradiol(one), 4OH-estradiol(one), and 16OH-estradiol(one) did not stimulate TNF secretion at 10(-10) M, but even inhibited its secretion at 10(-11) M. However, the combination of 16OH-estradiol(one) on one side and 2OH-estradiol(one) or 4OH-estradiol(one) on the other side markedly stimulated TNF secretion that was only observable in the presence of cortisol. In conclusion, at physiological concentrations, E2 and a combination of downstream estrogens stabilized or increased immune stimuli-induced TNF secretion. These effects are dependent on the presence of physiological concentrations of cortisol. This study underlines the proinflammatory role of E2, which is probably dependent on conversion to a proinflammatory cocktail of downstream estrogens and the presence of cortisol.

Adult↗
PubMed2006

Inflammation and sex hormone metabolism.

The incidence of autoimmune diseases is higher in females than in males. In both sexes, adrenal hormones, that is, glucocorticoids, dehydroepiandrosterone (DHEA), and androgens, are inadequately low in patients when compared to healthy controls. Hormonally active androgens are anti-inflammatory, whereas estrogens are pro-inflammatory. Therefore, the mechanisms responsible for the alterations of steroid profiles in inflammation are of major interest. The local metabolism of androgens and estrogens may determine whether a given steroid profile found in a subject's blood results in suppression or promotion of inflammation. The steroid metabolism in mixed synovial cells, fibroblasts, macrophages, and monocytes was assessed. Major focus was on cells from patients with rheumatoid arthritis (RA), while cells from patients with osteoarthritis served as controls. Enzymes directly or indirectly involved in local sex steroid metabolism in RA are: DHEA-sulfatase, 3beta-hydroxysteroid dehydrogenase, 17beta-hydroxysteroid dehydrogenase, and aromatase (CYP19), which are required for the synthesis of sex steroids from precursors, 5alpha-reductase and 16alpha-hydroxylase, which can be involved either in the generation of more active steroids or in the pathways leading to depletion of active hormones, and 3alpha-reductase and 7alpha-hydroxylase (CYP7B), which unidirectionally are involved in the depletion of active hormones. Androgens inhibit aromatization in synovial cells when their concentration is sufficiently high. As large amounts of estrogens are formed in synovial tissue, there may be a relative lack of androgens. Production of 5alpha-reduced androgens should increase the local anti-inflammatory activity; however, it also opens a pathway for the inactivation of androgens. The data discussed here suggest that therapy of RA patients may benefit from the use of nonaromatizable androgens and/or the use of aromatase inhibitors.

Androgens↗
PubMed2006

Circadian rhythms: glucocorticoids and arthritis.

Circadian rhythms are driven by biological clocks and are endogenous in origin. Therefore, circadian changes in the metabolism or secretion of endogenous glucocorticoids are certainly responsible in part for the time-dependent changes observed in the inflammatory response and arthritis. More recently, melatonin (MLT), another circadian hormone that is the secretory product of the pineal gland, has been found implicated in the time-dependent inflammatory reaction with effects opposite those of cortisol. Interestingly, cortisol and MLT show an opposite response to the light. The light conditions in the early morning have a strong impact on the morning cortisol peak, whereas MLT is synthesized in a strictly nocturnal pattern. Recently, a diurnal rhythmicity in healthy humans between cellular (Th1 type) or humoral (Th2 type) immune responses has been found and related to immunomodulatory actions of cortisol and MLT. The interferon (IFN)-gamma/interleukin (IL)-10 ratio peaked during the early morning and correlated negatively with plasma cortisol and positively with plasma MLT. Accordingly, the intensity of the arthritic pain varies consistently as a function of the hour of the day: pain is greater after waking up in the morning than in the afternoon or evening. The reduced cortisol and adrenal androgen secretion, observed during testing in rheumatoid arthritis (RA) patients not treated with glucocoticoids, should be clearly considered as a "relative adrenal insufficiency" in the presence of a sustained inflammatory process, and allows Th1 type cytokines to be produced in higher amounts during the late night. In conclusion, the right timing (early morning) for the glucocorticoid therapy in arthritis is fundamental and well justified by the circadian rhythms of the inflammatory mechanisms.

Animals↗
PubMed2006

Anti-TNF and sex hormones.

Whenever serum estrogen concentrations are normal in rheumatoid arthritis (RA) patients, lower androgen concentrations (i.e., testosterone, androstenedione, and dehydroepiandrosterone sulfate [DHEAS]) are detected in the serum as well as in the synovial fluid of male and female RA patients. The presence in the RA synovial fluid of a significant altered sex hormone balance resulting in lower immunosuppressive androgens and higher immuno-enhancing estrogens, might determine a favorable condition for the development of the immunomediated RA synovitis. The inflammatory cytokines (i.e., TNF-alpha), particularly increased in RA synovitis, are able to markedly stimulate the aromatase activity in peripheral tissues and, therefore, induce the peripheral metabolism from androgens to estrogens. The effects of TNF blockers (and generally of anticytokine agents) on peripheral sex hormone levels seem exerted in a faster way at the level of the RA synovial tissue (before any influence on serum levels) where they seem to block the conversion from androgens (anti-inflammatory) to estrogens (proinflammatory) induced by aromatase. Therefore, the beneficial effects of restoring synovial androgens might be clinically more evident in male RA patients (as recently observed in ANTARES study) since they suffer more for the lack of androgens (anti-inflammatory) on account of the action of TNF-alpha on peripheral hormonal conversion. However, therapy (3 months) with anti-TNF did not change serum levels of typical sex hormones in patients with RA, although baseline values were largely different from controls. In patients with at least long-standing RA, this indicates that alterations of serum sex hormones and altered activity of respective converting enzymes are imprinted for a long-lasting period over at least 12 weeks.

Animals↗
PubMed2006

Leptin is a link between adipose tissue and inflammation.

Leptin is a hormone of the pluripotent white adipose tissue and confers a multitude of regulatory functions within the organism. It controls the energy storage, lipoprotein metabolism, acute phase reactants, sex hormones and glucocorticoid metabolism, and immune function. In this review, we describe these multiple functions of leptin, the regulation of leptin expression, and how leptin can modulate the immune system via direct and indirect mechanisms. We show how leptin can be a link between the adipose tissue and inflammation.

Adipose Tissue↗
PubMed2005

[Stress, hormones, and neuronal signals in the pathophysiology of rheumatoid arthritis. The negative impact on chronic inflammation].

This review demonstrates that hormonal and neuronal factors, which are released during stressful situations, can unfavorably influence the two chronic diseases of rheumatoid arthritis and juvenile idiopathic arthritis. Noradrenaline and cortisol are in the focus of this review. In the said two chronic inflammatory diseases, it is obvious that apart from the immune system also the endocrine and nervous system play an essential role in the stress-induced initiation and aggravation of these diseases.

Adult↗
PubMed2005

Potencies of topical glucocorticoids to mediate genomic and nongenomic effects on human peripheral blood mononuclear cells.

Several different genomic and nongenomic mechanisms are known to mediate the important anti-inflammatory and immunomodulatory effects of glucocorticoids (GC). Genomic effects are the most important while the clinical relevance of nongenomic actions is still a matter of debate. We therefore investigated whether beclometasone and clobetasol are particularly suitable for topical application because of their specific spectrum of genomic and nongenomic actions. For these purposes we compared effects on oxygen consumption as measured with a Clark electrode (nonspecific nongenomic glucocorticoid effects), on interleukin-6 synthesis by means of ELISA (genomic effects) and on apoptosis using flow cytometry (nongenomic and genomic effects) in quiescent and mitogen-stimulated PBMC. Beclometasone and clobetasol indeed had stronger effects on the oxygen consumption of quiescent and stimulated cells at lower concentrations (10(-10) and 10(-8) M) but were less potent at higher concentrations (10(-5) and 10(-4) M) in comparison with dexamethasone. Also in terms of genomic potency, topical GC were more effective than dexamethasone at 10(-10) and 10(-8) M but gave similar results at higher concentrations. The ability of all three GC to induce apoptosis was found to be concentration-dependent and similar at concentrations between 10(-8) and 10(-5) M. But, compared with 10(-4) M dexamethasone, topical GC at 10(-4) M were significantly more effective at inducing apoptosis in both PBMC and Jurkat T-cells. These results show that topical GC have different concentration--(genomic/nongenomic) effect--ratios compared with dexamethasone: besides to the well-known genomic effects there are also significant nongenomic effects of topical glucocorticoids that already at low concentrations might be more therapeutically relevant in certain clinical conditions than currently assumed.

Anti-Inflammatory Agents↗
PubMed2005

Enhanced Y1-receptor-mediated vasoconstrictive action of neuropeptide Y (NPY) in superior mesenteric arteries in portal hypertension.

BACKGROUND/AIMS: Vascular hyporeactivity to catecholamines contributes to arterial vasodilation and hemodynamic dysregulation in portal hypertension. Neuropeptide Y (NPY) is a sympathetic neurotransmitter facilitating adrenergic vasoconstriction via Y1-receptors on the vascular smooth muscle. Therefore, we investigated its role for vascular reactivity in the superior mesenteric artery (SMA) of portal vein ligated (PVL) and sham operated rats. METHODS: In vitro perfused SMA vascular beds of rats were tested for the cumulative dose-response to NPY dependent on the presence and level of alpha1-adrenergic vascular tone (methoxamine MT: 0.3-10 microM). Moreover, the effect of NPY (50 nM) on vascular responsiveness to alpha1-adrenergic stimulation (MT: 0.3-300 microM) was evaluated. Y1-receptor function was tested by Y1-selective inhibition using BIBP-3226 (1 microM). RESULTS: NPY dose-dependently and endothelium-independently enhanced MT-pre-constriction in SMA. This potentiation was increasingly effective with increasing adrenergic pre-stimulation and being more pronounced in PVL rats as compared to sham rats at high MT concentrations. NPY enhanced vascular contractility only in PVL rats correcting the adrenergic vascular hyporeactivity. Y1-receptor inhibition completely abolished NPY-evoked vasoconstrictive effects. CONCLUSIONS: NPY endothelium-independently potentiates adrenergic vasoconstriction via Y1-receptors being more pronounced in portal hypertension improving mesenteric vascular contractility and thereby correcting the splanchnic vascular hyporeactivity. This makes NPY a superior vasoconstrictor counterbalancing arterial vasodilation in portal hypertension.

Adrenergic alpha-Agonists↗
PubMed2005

Adrenal and gonadal hormone variations during a febrile attack in a woman with tumor necrosis factor receptor-associated periodic syndrome.

CONTEXT: TNF-receptor-associated periodic syndrome (TRAPS) is a hereditary fever syndrome that results from mutations in the TNF-receptor superfamily 1A gene (TNFRSF1A). It is characterized by periodic fever, arthralgia, abdominal pain, myalgia, headache, and skin lesions. OBJECTIVE: Because adrenal and gonadal hormone cascades are modulated by TNF, this study aimed to investigate specific hormones and enzyme steps during an attack phase in a woman with TRAPS. DESIGN: Morning blood samples were taken from a 38-yr-old woman before, during, and after the febrile episode in the late luteal, menstrual, and early follicular phase of the menstrual cycle, respectively. RESULTS: Serum cortisol levels were markedly increased throughout the entire observation period and demonstrated a dip during the attack phase. In contrast, serum levels of dehydroepiandrosterone and 17-hydroxyprogesterone demonstrated a sharp rise during the febrile episode. Dehydroepiandrosterone in relation to androstenedione or cortisol was increased. Indicative of aromatase activation, estrone and 17beta-estradiol demonstrated a marked increase during the attack phase. CONCLUSION: This study suggests that some important steroid hormone-conversion steps are activated (aromatase) and inhibited (second step of the P450c17 and the 3beta-hydroxysteroid dehydrogenase) during the inflammatory attack phase in a TRAPS patient. These changes of enzyme pathways are typical on the basis of increased TNF signaling.

17-alpha-Hydroxyprogesterone↗
PubMed2005

Ablation of the sympathetic nervous system decreases gram-negative and increases gram-positive bacterial dissemination: key roles for tumor necrosis factor/phagocytes and interleukin-4/lymphocytes.

The sympathetic nervous system is intensely activated during bacteremia, but its immediate influence on the bacterial tissue burden remains unclear. We demonstrate that prior ablation of the sympathetic nervous system decreases this dissemination of Pseudomonas aeruginosa or Escherichia coli through a mechanism of increased secretion of peritoneal tumor necrosis factor, improved phagocytic response of peritoneal cells, and increased influx of monocytes into the peritoneal cavity. When gram-positive Staphylococcus aureus strains were used, sympathectomy increased the bacterial tissue burden, which was caused by a reduction in corticosterone tonus, and decreased both interleukin-4 secretion from peritoneal cells and the influx of lymphocytes into the peritoneal cavity. In both models, the peritoneal wall was the critical border for systemic infection. These results show the dual role of the sympathetic nervous system in sepsis. It can be favorable or unfavorable, depending on the innate immune effector mechanisms necessary to overcome infection.

Animals↗