Glucocorticoids, master modulators of the thymic catecholaminergic system?

Stress often occurs during toxicity studies. The perception of sensory stimuli as stressful primarily results in catecholamine release and activation of the hypothalamic-pituitary-adrenal (HPA) axis to increase serum glucocorticoid concentrations. Downstream effects of these neuroendocrine signals may include decreased total body weights or body weight gain; food consumption and activity; altered organ weights (e.g., thymus, spleen, adrenal); lymphocyte depletion in thymus and spleen; altered circulating leukocyte counts (e.g., increased neutrophils with decreased lymphocytes and eosinophils); and altered reproductive functions. Typically, only some of these findings occur in a given study. Stress responses should be interpreted as secondary (indirect) rather than primary (direct) test article-related findings. Determining whether effects are the result of stress requires a weight-of-evidence approach. The evaluation and interpretation of routinely collected data (standard in-life, clinical pathology, and anatomic pathology endpoints) are appropriate and generally sufficient to assess whether or not changes are secondary to stress. The impact of possible stress-induced effects on data interpretation can partially be mitigated by toxicity study designs that use appropriate control groups (e.g., cohorts treated with vehicle and subjected to the same procedures as those dosed with test article), housing that minimizes isolation and offers environmental enrichment, and experimental procedures that minimize stress and sampling and analytical bias.This article is a comprehensive overview of the biological aspects of the stress response, beginning with a Summary (Section 1) and an Introduction (Section 2) that describes the historical and conventional methods used to characterize acute and chronic stress responses. These sections are followed by reviews of the primary systems and parameters that regulate and/or are influenced by stress, with an emphasis on parameters evaluated in toxicity studies:

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“…Effects of catecholamines on T-lymphocyte development may be modulated by glucocorticoids (Pilipovic et al 2010).…”

Section: Catecholaminesmentioning

confidence: 99%

Interpreting Stress Responses during Routine Toxicity Studies

et al. 2013

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“…There is an increasing body of evidence supporting the concept of communication between the body's major adaptive systems (nervous, endocrine, and immune) as a complex network, wherein a signaling molecule can arise from multiple sources to act at multiple targets, and in which signaling molecules are connected to one another in multiple ways and at multiple levels. In favor of this concept are findings showing an interplay between GCs and CAs in the tuning of thymopoiesis, 84 and in particular those findings pointing to putative points of intersections and crosstalk between GC and CA signaling (Fig. 1).…”

Section: Discussionmentioning

confidence: 99%

“…At present, there are no data to confirm GCs’ influence on CA bioavailability in the thymus (this research is in progress in our laboratory). However, we have demonstrated that β‐AR blockade with propranolol, a nonselective beta blocker, led to more pronounced effects on T cell development in previously adrenalectomized rats than in control animals 84 . This is consistent with data showing that in vivo coadministration of hydrocortisone (at a concentration that by itself did not alter the cAMP content of the thymus) with the β‐AR agonist isoproterenol induced a rapid, dose‐dependent increase in the mouse thymic cAMP content and enhanced the effects of isoproterenol on thymic atrophy 85 …”

Section: Glucocorticoid–catecholamine Communications In the Thymopoiementioning

confidence: 90%

“…In rats adrenalectomized 4 days prior to the beginning of 4‐day propranolol treatment, the increase in frequency of the most mature CD4 − CD8 + and CD4 + CD8 − TCRαβ high SP thymocytes was greater than the same treatment in nonadrenalectomized rats 84 . This most likely reflected not only changes in thymic CA bioavailability, but also alterations at the β‐AR level.…”

Section: Glucocorticoid–catecholamine Communications In the Thymopoiementioning

confidence: 91%

“…Corroborating the latter possibility are data indicating that GCs up‐regulate β‐AR expression and β‐AR−mediated CA action 79,85,90,91 . However, given that the rise in the frequency of CD8 + CD4 ‐ SP TCRαβ high cells following propranolol treatment was more pronounced in adrenalectomized than in nonadrenalectomized rats, it was assumed that differential effects of propranolol on T cell differentiation/maturation in adrenalectomized and nonadrenalectomized rats could not solely be ascribed to more efficient β‐AR blockade in adrenalectomized rats 84 . Considering that α 1 ‐AR–mediated signaling was shown to favor thymocyte differentiation/maturation toward a mature CD4 − CD8 + phenotype, 76 and that prolonged exposure of cardiac myocytes to norepinephrine led to diminished α 1 ‐AR expression, 92 one may speculate that α 1 ‐AR upregulation (due to prolonged decrease in norepinephrine bioavaiability in the thymus) led to preferential differentiation/maturation of CD4 + CD8 + DP thymocytes toward a CD4 − CD8 + TCRαβ high phenotype.…”

Section: Glucocorticoid–catecholamine Communications In the Thymopoiementioning

confidence: 99%

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Glucocorticoid–catecholamine interplay within the composite thymopoietic regulatory network

Pilipović

Radojević

Perišić

et al. 2012

Annals of the New York Academy of Sciences

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This paper highlights the multiple putative thymic and extrathymic points of intersection and interaction between glucocorticoids (GCs) and catecholamines (CAs)—the end‐point mediators of the major routes of communication between the brain and the immune system—in the context of intricate thymic T cell–developmental tuning. More specifically, we discuss in detail findings indicating that adrenal GCs can influence thymopoiesis by adjusting directly and/or indirectly (through modulation of pituitary and local ACTH synthesis) not only thymic GC synthesis, in a cell type–specific manner, but also thymic CA bioavailability (via altering CA outflow from sympathetic nerve endings and local CA synthesis), β and α1‐adrenoceptor (AR) expression, and/or AR‐mediated intracellular signal transduction in thymic cells. In addition, this short review points to GC‐ and CA‐sensitive stages along the multistep T cell–developmental journey and the possible effects of altered GC, and consequently CA signaling, on thymopoietic efficiency.

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End-point effector stress mediators in neuroimmune interactions: their role in immune system homeostasis and autoimmune pathology

et al. 2012

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Much evidence has identified a direct anatomical and functional link between the brain and the immune system, with glucocorticoids (GCs), catecholamines (CAs), and neuropeptide Y (NPY) as its end-point mediators. This suggests the important role of these mediators in immune system homeostasis and the pathogenesis of inflammatory autoimmune diseases. However, although it is clear that these mediators can modulate lymphocyte maturation and the activity of distinct immune cell types, their putative role in the pathogenesis of autoimmune disease is not yet completely understood. We have contributed to this field by discovering the influence of CAs and GCs on fine-tuning thymocyte negative selection and, in particular, by pointing to the putative CA-mediated mechanisms underlying this influence. Furthermore, we have shown that CAs are implicated in the regulation of regulatory T-cell development in the thymus. Moreover, our investigations related to macrophage biology emphasize the complex interaction between GCs, CAs and NPY in the modulation of macrophage functions and their putative significance for the pathogenesis of autoimmune inflammatory diseases.

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Glucocorticoids, master modulators of the thymic catecholaminergic system?

Cited by 5 publications

References 19 publications

Interpreting Stress Responses during Routine Toxicity Studies

Interpreting Stress Responses during Routine Toxicity Studies

Glucocorticoid–catecholamine interplay within the composite thymopoietic regulatory network

End-point effector stress mediators in neuroimmune interactions: their role in immune system homeostasis and autoimmune pathology

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