scholarly journals OR19-04 Glucocorticoid Production in the Nervous and Immune Systems: Evidence for a Local HPA Axis Homolog

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Melody Salehzadeh ◽  
Jordan Edward Hamden ◽  
Michael X Li ◽  
Hitasha Bajaj ◽  
Cathy Ma ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Hpa Axis ◽  
Anterior Pituitary ◽  
Adrenal Glands ◽  
Brain Regions ◽  
Lymphoid Organs ◽  
Thymocyte Development ◽  
Immune Systems ◽  
Immune System Development ◽  
Glucocorticoid Production

Abstract Glucocorticoid Production in the Nervous and Immune Systems: Evidence for a Local HPA Axis Homolog The hypothalamic-pituitary-adrenal (HPA) axis is a critical stress response system in vertebrates. The hypothalamus secretes corticotropin-releasing hormone (CRH), which binds its receptor (CRH-R1) in the anterior pituitary. The anterior pituitary then secretes adrenocorticotropic hormone (ACTH), which binds its receptor (MC2R) in the adrenal glands and stimulates secretion of glucocorticoids into the bloodstream. Glucocorticoids are critical modulators of neural and immune system development. During early development (postnatal day (PND) 2 to 12), mice show decreased adrenal glucocorticoid secretion at baseline and in response to stressors, termed the stress hyporesponsive period (SHRP) (1). Traditionally, glucocorticoids have been thought to be synthesized only in the adrenal glands. However, recent evidence demonstrates that glucocorticoids are also produced in extra-adrenal tissues, such as the brain and lymphoid organs (2). This may be of particular importance during the SHRP, as local production allows glucocorticoid modulation of specific tissues and cells, without general effects throughout the organism. Importantly, the factors that regulate local glucocorticoid production remain unknown. To study the regulation of local glucocorticoid production, we examined whether mediators of the HPA axis are locally expressed at baseline and in response to an immune stressor. We assessed systemic and local glucocorticoid levels in neonatal (PND5) C57BL/6J mice 4hr after an immune challenge with lipopolysaccharide (50µg/kg i.p.) or vehicle control. We examined blood, microdissected brain regions (prefrontal cortex, hippocampus, hypothalamus), and lymphoid organs (thymus, spleen, bone marrow). A panel of 7 steroids was measured via liquid chromatography tandem mass spectrometry (LC-MS/MS). Gene expression of Crh, Crh-R1, Pomc, and Mc2r was quantified via qPCR. Preliminary data indicate that corticosterone was 2-fold higher in tissues than in blood after an immune stressor. The thymus expressed all genes of interest, supporting the existence of a local HPA axis “homolog” in the thymus. Brain, spleen and bone marrow expressed a subset of the genes of interest. These exciting data demonstrate that all the mediators of the HPA axis are locally expressed within the thymus, likely to regulate thymocyte development and reactivity. Greater understanding of local glucocorticoid production will provide crucial insight into neural and immune development and function. Reference: (1) Sapolsky et al., Brain Res Rev. 1986 11(1):65–76. (2) Taves et al., Endocrinology. 2015 156(2):511–522.

Glucocorticoid production in lymphoid organs: Acute effects of lipopolysaccharide in neonatal and adult mice

Endocrinology ◽  
2021 ◽  
Author(s):  
Melody Salehzadeh ◽  
Jordan E Hamden ◽  
Michael X Li ◽  
Hitasha Bajaj ◽  
Ruolan S Wu ◽  
...  
Keyword(s):  
Hpa Axis ◽  
Adrenal Glands ◽  
Lymphoid Organs ◽  
Acute Effects ◽  
Steroidogenic Enzymes ◽  
Steroidogenic Enzyme ◽  
Adult Mice ◽  
Liquid Chromatography Tandem Mass ◽  
Glucocorticoid Production ◽  
Local Expression

Abstract Glucocorticoids (GCs) are critical modulators of the immune system. The hypothalamic-pituitary-adrenal (HPA) axis regulates circulating GC levels and is stimulated by endotoxins. Lymphoid organs also produce GCs; however, it is not known how lymphoid GC levels are regulated in response to endotoxins. We assessed whether an acute challenge of lipopolysaccharide (LPS) increases lymphoid levels of GCs, steroidogenic enzymes expression, and components of the HPA axis (e.g., CRH) expression. We administered LPS (50µg/kg i.p.) or vehicle control to male and female C57BL/6J neonatal (post-natal day (PND) 5) and adult (PND90) mice and collected blood, bone marrow, thymus, and spleen 4 hr later. We measured progesterone, 11-deoxycorticosterone (DOC), corticosterone, and 11-dehydrocorticosterone (DHC) via liquid chromatography tandem mass spectrometry (LC-MS/MS). We measured gene expression of key steroidogenic enzymes (Cyp11b1, Hsd11b1, and Hsd11b2) and HPA axis components (Crh, Crhr1, Pomc, and Mc2r) via qPCR. At PND5, LPS induced greater increases in steroid levels in lymphoid organs than in blood. In contrast, at PND90, LPS induced greater increases in steroid levels in blood than in lymphoid organs. Steroidogenic enzyme transcripts were present in all lymphoid organs, and LPS altered steroidogenic enzyme expression predominately in the spleen. Lastly, we detected transcripts of key HPA axis components in all lymphoid organs, and there was an effect of LPS in the spleen. Taken together, these data suggest that LPS regulates GC production by lymphoid organs, similar to its effects on the adrenal glands, and the effects of LPS might be mediated by local expression of CRH and ACTH.

Isoflurane stress induces glucocorticoid production in mouse lymphoid organs

2021 ◽  
Author(s):  
Jordan E Hamden ◽  
Melody Salehzadeh ◽  
Katherine M. Gray ◽  
Brandon J Forys ◽  
Kiran K Soma
Keyword(s):  
Adrenal Glands ◽  
Vehicle Control ◽  
Postnatal Period ◽  
Lymphoid Organs ◽  
Systemic Steroid ◽  
Potential Mechanism ◽  
Response To Stress ◽  
Glucocorticoid Production ◽  
Acute Stressor ◽  
Insight Into

Glucocorticoids (GCs) are secreted by the adrenal glands and locally produced by lymphoid organs. Adrenal GC secretion at baseline and in response to stressors is greatly reduced during the stress hyporesponsive period (SHRP) in neonatal mice (postnatal day (PND) 2-12). It is unknown whether lymphoid GC production increases in response to stressors during the SHRP. Here, we administered an acute stressor (isoflurane anesthesia) to mice before, during, and after the SHRP and measured systemic and local GCs via mass spectrometry. We administered isoflurane, vehicle control (oxygen), or neither (baseline) at PND 1, 5, 9, or 13 and measured progesterone and 6 GCs in blood, bone marrow, thymus, and spleen. At PND1, blood and lymphoid GC levels were high and did not respond to stress. At PND5, blood GC levels were very low and increased slightly after stress, while lymphoid GC levels were also low but, increased greatly after stress. At PND9, blood and lymphoid GC levels were similar at baseline and increased similarly after stress. At PND13, blood GC levels were higher than lymphoid GC levels at baseline, and blood GC levels showed a greater response to stress. These data demonstrate the remarkable plasticity of GC physiology during the postnatal period, show that local steroid levels do not reflect systemic steroid levels, provide insight into the SHRP, and identify a potential mechanism by which early-life stressors can alter immunity in adulthood.

VEGF inhibits T-cell development and may contribute to tumor-induced immune suppression

Blood ◽  
2003 ◽  
Vol 101 (12) ◽  
pp. 4878-4886 ◽  
Author(s):  
Joyce E. Ohm ◽  
Dmitry I. Gabrilovich ◽  
Gregory D. Sempowski ◽  
Ekaterina Kisseleva ◽  
Kelly S. Parman ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cell ◽  
Cancer Patients ◽  
Thymocyte Development ◽  
Thymic Atrophy ◽  
Fetal Thymic Organ Culture ◽  
Immune Deficiencies ◽  
Thymocyte Apoptosis ◽  
Advanced Stage Cancer ◽  
Endothelial Growth Factor

AbstractT-cell defects and premature thymic atrophy occur in cancer patients and tumor-bearing animals. We demonstrate that exposure of mice to recombinant vascular endothelial growth factor (VEGF) at concentrations similar to those observed in advanced stage cancer patients reproduces this profound thymic atrophy and is highlighted by a dramatic reduction in CD4+/CD8+ thymocytes. We find that VEGF does not induce thymocyte apoptosis, but instead rapidly decreases the number of the earliest observable progenitors in the thymus. VEGF does not inhibit thymocyte development in fetal thymic organ culture, further suggesting a prethymic effect. We also demonstrate that bone marrow progenitors from animals infused with recombinant VEGF and transferred to irradiated untreated animals recolonize the thymus more efficiently than progenitors from control animals. This suggests that VEGF exposure is associated with an increased population of thymus-committed progenitors in the bone marrow. We hypothesize that pathophysiologically relevant concentrations of VEGF may block the differentiation and/or emigration of these progenitors resulting in the observed thymic atrophy. Removal of VEGF via cessation of infusion or adoptive transfer of progenitors to a congenic host induces a preferential commitment of lymphoid progenitors to the T lineage and results in a restoration of the normal composition and cellularity of the thymus. These data demonstrate that at pathophysiologic concentrations, VEGF interferes with the development of T cells from early hematopoetic progenitor cells and this may contribute to tumor-associated immune deficiencies.

scholarly journals Green Brazilian Propolis Action on Macrophages and Lymphoid Organs of Chronically Stressed Mice

2008 ◽  
Vol 5 (1) ◽  
pp. 71-75 ◽  
Author(s):  
Fabiane Missima ◽  
José Maurício Sforcin
Keyword(s):  
Bone Marrow ◽  
Adrenal Glands ◽  
Well Being ◽  
Peritoneal Macrophages ◽  
Histopathological Analysis ◽  
No Production ◽  
Generic Term ◽  
Brazilian Propolis ◽  
Immunomodulatory Action ◽  
New Research

Stress is a generic term that summarizes how psychosocial and environmental factors influence physical and mental well-being. The interaction between stress and immunity has been widely investigated, involving the neuroendocrine system and several organs. Assays using natural products in stress models deserve further investigation. Propolis immunomodulatory action has been mentioned and it has been the subject of scientific investigation in our laboratory. The aim of this study was to evaluate if and how propolis activated macrophages in BALB/c mice submitted to immobilization stress, as well as the histopathological analysis of the thymus, bone marrow, spleen and adrenal glands. Stressed mice showed a higher hydrogen peroxide (H2O2) generation by peritoneal macrophages, and propolis treatment potentiated H2O2generation and inhibited nitric oxide (NO) production by these cells. Histopathological analysis showed no alterations in the thymus, bone marrow and adrenal glands, but increased germinal centers in the spleen. Propolis treatment counteracted the alterations found in the spleen of stressed mice. New research is being carried out in order to elucidate propolis immunomodulatory action during stress.

scholarly journals Corrective effects of original bioflavonoid complex in the cyclophosphamide-induced immunity disorders

2021 ◽  
Vol 22 (6) ◽  
pp. 1111-1120
Author(s):  
I. A. Goldina ◽  
E. V. Markova ◽  
I. A. Orlovskaya ◽  
L. B. Toporkova ◽  
V. A. Kozlov
Keyword(s):  
Bone Marrow ◽  
Immune Response ◽  
Cellular Immune Response ◽  
Proliferative Activity ◽  
Lymphoid Organs ◽  
Delayed Type Hypersensitivity ◽  
Relative Mass ◽  
Hematopoietic Progenitors ◽  
Hematopoietic Stem ◽  
Cellular Immune

Our aim was to evaluate immunomodulatory properties of an original bioflavonoid complex in experimental immune disturbances induced by cyclophosphamide (Cy). We have studied morphometric indexes of thymus and spleen, as well as blood leukocyte counts, cell proliferative activity in lymphoid organs, delayed hypersensitivity responses to T cell-dependent antigen, along with differentiation activity of bone marrow stem cells in experimental animals during Cy-induced immune suppression after a course of bioflavonoid treatment. Suspension of the bioflafonoid complex was introduced to the male mice (СВАхC57Bl/6)F1 aged 12- 14 weeks at a daily dose of 2 mg/animal (80 mg/kg), per os, using gastric catheter, over 14 days. Cytostatic immunosuppression was produced by a single intraperitoneal Cy injection. Proliferative activity of spleen and thymic cells was determined by standard method with Н3 -thymidine incorporation in the 72-h cell culture. Cellular immune response was assayed by the degree of delayed-type hypersensitivity development in response to sheep erythrocytes. The number of hematopoietic progenitors was evaluated by culturing bone marrow cells in methylcellulose-based medium. The experiments have shown mitigation of immunosuppressive effects induced by Cy, in the course of bioflavonoid complex treatment, with respect to absolute and relative mass of lymphoid organs and leukocyte numbers in peripheral blood. Moreover, we have demonstrated decreased effects of Cy treatment upon the spontaneous activity of spleen cells, mitogen-induced thymocyte and splenocyte proliferation, intensivity of delayed-type hypersensitivity response that reached the values of intact animals. Following the course of bioflavonoids, we have revealed an increase in early hematopoietic progenitors. Alleviation of Cy-induced suppressive effects upon cellular immune response, proliferation rates of immune cells, as well as stimulation of hematopoietic stem cell functions suggest a sufficient capacity of the original bioflavonoid complex for modulation of immunity and hematopoiesis, thus presenting experimental proofs for its potential usage as an adjuvant treatment of the patients with malignant diseases.

scholarly journals Anterior pituitary trophic responses to dexamethasone withdrawal and repeated dexamethasone exposures

2001 ◽  
Vol 169 (2) ◽  
pp. 263-270 ◽  
Author(s):  
LA Nolan ◽  
A Levy
Keyword(s):  
Hpa Axis ◽  
Anterior Pituitary ◽  
Pituitary Cells ◽  
Duration Of Treatment ◽  
Glucocorticoid Treatment ◽  
Initial Exposure ◽  
Male Wistar Rats ◽  
Anatomic Basis ◽  
Delayed Recovery ◽  
Trophic Responses

Glucocorticoid withdrawal, depending on the dose and duration of treatment, results in a transient but sometimes prolonged reduction in hypothalamo-pituitary-adrenal (HPA) axis secretory responsiveness. As the anatomic basis of HPA axis suppression remains uncertain, we have directly examined changes in trophic activity within the rat anterior pituitary gland following dexamethasone withdrawal and re-treatment. Treatment of adrenalectomised, male Wistar rats with dexamethasone results in a discrete, highly significant burst of apoptosis in the anterior pituitary with concurrent suppression of mitosis. Despite a surge in mitotic activity immediately after dexamethasone withdrawal, calculated total anterior pituitary cell populations remain below that seen in untreated adrenalectomised controls. Repeated exposures to dexamethasone show that the dexamethasone-sensitive cell population that is deleted by apoptosis is partially but not completely restored. As the amplitude of apoptotic bursts induced by second and third dexamethasone exposures are similar but smaller than that induced by initial exposure, it appears that the very first exposure to dexamethasone deletes a subset of anterior pituitary cells that are either not restored at all, or are only replaced very slowly. The reduced proportion of corticotrophs contributing to the increase in mitotic index after dexamethasone withdrawal corroborates this. Although continued cell turnover within the pituitary predicts that the absolute cellular deficit would diminish with time, the effects seen may contribute to the delayed recovery of pituitary axis function following cessation of glucocorticoid treatment.

Testosterone metabolites associated with cytosol receptors and nuclei of anterior pituitary and various brain regions

1978 ◽  
Vol 9 (3) ◽  
pp. 257-264 ◽  
Author(s):  
Noma Keizo ◽  
Nakao Kiyohide ◽  
Sato Bunzo ◽  
Seki Tokuichko ◽  
Hanasaki Nobuo ◽  
...  
Keyword(s):  
Anterior Pituitary ◽  
Brain Regions ◽  
Testosterone Metabolites

Evaluation of Neuroendocrine and Immunological Parameters in Animals Following Chronic Combined Exposure to Xenobiotics

2021 ◽  
pp. 47-51
Author(s):  
AI Smolyagin ◽  
IV Mikhaylova ◽  
EV Ermolina ◽  
AA Stadnikov ◽  
VM Boev
Keyword(s):  
Bone Marrow ◽  
Wistar Rats ◽  
The Body ◽  
Combined Exposure ◽  
Immune Systems ◽  
Cell Counts ◽  
Apoptotic Protein ◽  
Occupational Setting ◽  
Male Wistar Rats ◽  
Ifn Γ

Background: A high prevalence of chromium and benzene compounds in the environment associated with motor vehicle and industrial operations arouses interest in the study of these xenobiotics in a long-term experiment. The objective of this work was to analyze effects of a chronic combined exposure to chromium and benzene on the hypothalamic-pituitary-adrenocortical (HPA) and immune systems of male Wistar rats. Materials and methods: Eighty male Wistar rats were administered potassium dichromate and benzene with drinking water in doses equaling one maximum permissible concentration (MPC) during 135 days. The hypothalamus, pituitary gland, adrenal glands, thymus, and spleen were then studied using morphometric, histological, and electron microscopy methods. The streptavidin-biotin peroxidase method was used to determine the expression of pro-apoptotic protein p53 and anti-apoptotic protein bcl2. We also measured the body, thymus and spleen weights of animals, nucleated cell counts in the thymus, spleen, and bone marrow and evaluated the cellular composition of the spleen and bone marrow as well as spontaneous and concanavalin A-induced secretion of interferon gamma (IFN-γ), IL-4, IL-6, and IL-10 cytokines by splenocytes. Results: We established an adverse effect of the exposure on the HPA function expressed in the activation of its secretory activity, blocking the release of hypothalamic neuropeptides at the level of the neurohypophysis and leading to ultrastructural damage to the neurosecretory cells of the hypothalamus, pituitary adenocytes and adrenal cortical cells, as well as in an increase in the programmed death of thymocytes. We also observed a decrease in the thymus weight and thymocyte counts and a complex of structural and functional changes indicating the status of its accidental involution in the exposed rats. The revealed decrease in the splenocyte count in the experimental group was accompanied by an increase in the size of the white spleen pulp. An increase in the induced production of the main immunoregulatory cytokines IFN-γ and IL-4 by splenocytes was found. Conclusion: Our findings can be used to analyze impairments of the HPA and immune systems in workers with a chronic combined exposure to benzene and chromium compounds in the occupational setting.

Factors Influencing Diuresis in Rats Following Total-Body X-Irradiation

1957 ◽  
Vol 189 (1) ◽  
pp. 11-14 ◽  
Author(s):  
E. Irene Pentz ◽  
Robert J. Hasterlik
Keyword(s):  
Adrenal Cortex ◽  
Anterior Pituitary ◽  
Adrenal Glands ◽  
Anterior Lobe ◽  
Posterior Pituitary ◽  
Cortical Control ◽  
Factors Influencing ◽  
X Irradiation ◽  
Diuretic Response ◽  
Total Body

An immediate diuresis has been observed in rats exposed to total-body x-irradiation ranging between 100 and 400 r. Since the highest dosage produced more consistent results, it was used in conjunction with extirpation of various glands and other organs in an effort to determine the mechanism that responds so promptly to x-irradiation. The anterior pituitary and the adrenal cortex are of prime importance in this reaction. Removal of the anterior lobe of the pituitary or removal of the adrenal glands is sufficient to completely inhibit diuresis following 400 r x-irradiation. This diuretic response is not dependent upon the presence of the posterior pituitary since animals having only this gland removed became diuretic following exposure to 400 r. The evidence suggests that the release of antidiuretic substances from tissues other than the posterior pituitary is under anterior pituitary-adrenal cortical control.

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