Immunosuppressants, rheumatic and gastrointestinal topics
Evelyne Jacqz-Aigrain, Imti Choonara in Paediatric Clinical Pharmacology, 2021
Mechanism of action. The effects are mediated through corticosteroid receptors, members of the large steroid-nuclear receptor family that also include receptors for mineralocorticoids, sexual hormones, vitamin D, thyroid hormone and retinoic acid. The corticosteroid receptor is located in the cytoplasm and enters the nucleus of the cell after activation by different hormones. The corticosteroid receptor regulates gene transcription in target genes by binding, as a homodimer, to corticosteroid responsive elements. Corticosteroids enhance the transcription of several genes, limiting expression of inflammatory cytokines through transcription factors such as NK-kB and AP-1, associated with the induction of numerous genes, encoding for cytokines, chemokines and adhesion molecules (TNF-α, IL-1β, IL-6, ICAM-1), and resulting in the anti-inflammatory effects of corticosteroids. For some genes (IL-11, GM-CSF and cyclooxygenase), regulation of expression by corticosteroids is both transcriptional and posttranscriptional [38].
Stress-Responsive Neurohormones in Depression and Anxiety
Siegfried Kasper, Johan A. den Boer, J. M. Ad Sitsen in Handbook of Depression and Anxiety, 2003
Blockade of GR as a treatment strategy has been poorly studied due to the lack of specific antagonists. Preliminary results suggested that mifepristone (RU486) may be a useful treatment approach in major depression [129]. At the moment it is not fully clear how disturbed corticosteroid-receptor signaling can be influenced therapeutically. Conservatively, administration of a CRH-R1 antagonist is expected to shorten the onset of coadministered antidepressants. Such drugs may also work as antidepressants when administered as monotherapy [120]. Similarly, GR antagonists might not be effective enough as monotherapy, but they may be a worthwhile adjunct to antidepressants. Perhaps the most intriguing approach is the administration of GR antagonists to patient with psychotic depression. It has been submitted by Schatzberg and coworkers [130] that hypercortisolemia enhances dopaminergic transmission to an extent that results clinically in psychotic symptoms. Thus suppressing cortisol effects at GR may limit this dopamine excess and thus resolve psychotic symptoms. It is of note that psychotic depression is almost always associated with HPA overactivity.
Hormones as Immune Modulating Agents
Thomas F. Kresina in Immune Modulating Agents, 2020
Apparently, glucocorticoids also exert some immunoregulatory effect through the mineralocorticoid receptor (also called type I corticosteroid receptor). This receptor participated in the cortisol-induced inhibition of interleukin-1 receptor antagonist by LPS stimulated monocytes. The type I receptor antagonist spironolactone and the type II receptor antagonist RU38486 both partially reversed this inhibitory effect. Aldosterone was also inhibitory; it was blocked by spironolactone [205].
The effects of ovarian hormones on stressor-induced hormonal responses, glucocorticoid receptor expression and translocation, and genes related to receptor signaling in adult female rats
Published in Stress, 2018
Matthew R. Green, Marina L. Marcolin, Cheryl M. McCormick
We hypothesized that estradiol would increase HPA activity and that we would see a corresponding reduction in GR expression and activity, which we assessed by measuring cytosolic and nuclear GR in the hippocampus before and after acute restraint stress. Consistent with the literature (Handa & Weiser, 2014) and with our hypothesis, ovariectomy reduced baseline and post-stress concentrations of corticosterone relative to gonadally-intact females and treatment of estradiol reversed the effect of ovariectomy. Moreover, ovariectomy increased cytosolic GR relative to several estradiol-treated groups and this group was the only one to have a stress-induced decrease in cytosolic GR, which supported our hypothesis that estradiol restricts GR expression and activity. As expected, stress increased nuclear GR expression, but contrary to our hypothesis we did not see an effect of estradiol treatment. Therefore, we found partial evidence that estradiol reduces feedback by restricting GR expression and activity. Contrary to our hypotheses, there were no differences in the expression of genes that code for corticosteroid receptors or co-chaperones and co-activators known to modulate corticosteroid receptor activity.
Targeted anti-IL-13 therapies in asthma: current data and future perspectives
Published in Expert Opinion on Investigational Drugs, 2018
Polyxeni Ntontsi, Evgenia Papathanassiou, Stelios Loukides, Petros Bakakos, Georgios Hillas
Patients with severe asthma often require high doses of both inhaled corticosteroids (ICS) and oral corticosteroids to achieve disease control occasionally with modest results. The levels of IL-13 have been correlated with corticosteroid responsiveness. Naseer et al. utilized a 7-day oral corticosteroid treatment and demonstrated that IL-13 mRNA levels persisted in bronchial biopsy specimens from corticosteroid nonresponsive patients whereas levels in corticosteroid responsive patients receded. Moreover, the latter group experienced an improvement in pulmonary function tests [33]. Interestingly IL-13 levels remained elevated when patients with uncontrolled asthma are treated with either inhaled or/and systemic CS (corticosteroids) [34]. It is now clear that IL-13 remains elevated in corticosteroid insensitive asthma, but not in sensitive asthma [35,36]. As a matter of fact treatment with corticosteroids can repress IL-13 gene transcription both directly and indirectly [37,38]. On the other hand, an in vitro model demonstrated that IL-13 reduces corticosteroid receptor binding affinity and hence impaired response to corticosteroid therapy can be possibly explained [39]. Interestingly, Kraft et al. reported that airway macrophages are responsible for reducing responsiveness to corticosteroid treatment in patients with nocturnal asthma through an IL-13-mediated mechanism [40].
Female HPA axis displays heightened sensitivity to pre-pubertal stress
Published in Stress, 2020
Nichola M. Brydges, Caroline Best, Kerrie L. Thomas
Animal studies demonstrate that ELS has profound implications for later HPA axis function. Prenatal and early post-natal stressors alter basal and stress-induced corticosterone release from the adrenal glands, brain corticosteroid receptor (GR and MR) expression, as well as expression of AVP and OXT in a timing and sometimes sex-specific manner (Llorente et al., 2011; Lupien, McEwen, Gunnar, & Heim, 2009; Neumann & Landgraf, 2019; Schroeder, Notaras, Du, & Hill, 2018; Tobon, Jeffrey, & Nemeroff, 2018). However, despite well-established sex differences in the HPA axis, comparatively few preclinical studies include male and female animals. Compared to the prenatal and post-natal periods, less is known about the effects of stress experienced in the post-weaning, pre-pubertal phase (PPS), a time-point suggested as more akin to human childhood (Brydges, 2016). The limbic system and prefrontal cortex are undergoing maturation during this period, areas which are crucial for cognition and emotion and are extremely stress reactive due to high densities of CR, particularly in the hippocampal formation (Herman, 1993).
Related Knowledge Centers
- Cortisol
- Glucocorticoid
- Glucocorticoid Receptor
- Mineralocorticoid
- Nuclear Receptor
- Corticosteroid
- Receptor
- Mineralocorticoid Receptor
- Aldosterone
- Membrane Glucocorticoid Receptor