Transcriptional pattern analysis of adrenergic immunoregulation in mice. Twelve hours norepinephrine treatment alters the expression of a set of genes involved in monocyte activation and leukocyte trafficking
Introduction
Neuroendocrine immunoregulation is afflicted with a high degree of complexity. The brain, the endocrine and immune systems are all “dissipative systems” with a high degree of freedom in their reaction to a given external or internal stimulus. This can account for contradictory or unpredictable results, particularly in the in vivo situation.
A good example to illustrate the complexity of neuro-immune interactions is adrenergic immunomodulation, where the quantitative and qualitative outcome depends not only on dose and duration of the catecholamine stimulus, but also importantly on the stage of differentiation and/or activation of the different cells of the immune system (Haas and Schauenstein, 2001). Furthermore, catecholamines can act on immune functions in vivo in different ways, e.g. by changing the release of and/or receptivity to cytokines, or by changes in leukocyte trafficking thereby modulating the number of cells that participate in a given immune response (Benschop et al., 1996, Madden, 2001, Murray et al., 1993). The majority of the data so far suggest immunosuppressive effects due to beta-adrenergic stimulation and activation of cyclic AMP in immune cells (Sanders and Straub, 2002, Kohm and Sanders, 2001). However, several reports strongly suggest also immunoregulatory alpha-adrenergic mechanisms (Cupic et al., 2001), particularly in the in vivo situation (Felsner et al., 1995, Rouppe van der Voort et al., 2000). To make things even more confusing, it appears that pronounced species and strain differences are further complicating the picture.
A powerful strategy to tackle the problem of complexity should be to apply molecular multiparameter analysis techniques that allow recognizing changes in patterns of multiple components, instead of putting together single parameter observations, as has mainly been done so far.
Our group is interested in in vivo immunoregulatory effects of long term adrenergic stress. As experimental model we use the subcutaneous implantation of catecholamine containing retard tablets with a defined release to induce a hypercatecholaminemia in experimental animals corresponding to values observed under physiological stress conditions (Stevenson et al., 2001, Felsner et al., 1992, Felsner et al., 1995). In the present study we applied for the first time molecular techniques that allow to define the impact of a 12-h treatment with norepinephrine (NE) on the transcription of multiple, immunologically relevant genes in the mouse.
Section snippets
Animals
Male Balb/c mice were purchased at an age of 4–5 weeks from the Institute for Experimental Animal Breeding, Medical Faculty, University of Vienna, Austria, and maintained three or four animals per plastic cage under a 12/12 h light/dark cycle with laboratory chow and water ad libitum. After arrival they were accommodated to our facilities for at least 1 week before they were used at ages of 6–8 weeks.
Drugs and catecholamine treatment
l-Noaradrenaline bitartrate (NE), Propranolol-hydrochloride, Nadolol and
Results
In accordance with previous data in the rat model (Felsner et al., 1995), the noradrenergic treatment induced a significant loss in body weight of more than 10% and a significantly reduced relative organ weight of the spleen, which served as markers for the increased adrenergic tone (data not shown). Furthermore, also in line with previous experiences (Stevenson et al., 2001), significant changes occurred in WBC. The number of neutrophilic granulocytes significantly increased, whereas the
Discussion
In several previous studies we have used s.c. implanted retard tablets to investigate in vivo effects of long-term enhanced peripheral catecholamines on immune functions of the rat. The main result of this work was that a long term treatment with epinephrine or NE significantly suppressed the responsiveness of T cells only with concomitant blockade of beta-receptors (Felsner et al., 1995, Felsner et al., 1992, Liebmann et al., 1996, Stevenson et al., 2001). Using selective agonists, the
Acknowledgements
The helpful advice of Dr. Eva Roblegg and the technical assistance of Elvira Kloibhofer and Elfgard Heintz is gratefully acknowledged.
This study was supported by the Austrian Science Fund Project P 16060.
References (25)
- et al.
Catecholamine-induced leukocytosis: early observations, current research, and future directions
Brain Behav. Immun.
(1996) - et al.
Immunomodulatory effect of xylazine, an alpha(2) adrenergic agonist, on rat spleen cells in culture
J. Neuroimmunol.
(2001) - et al.
Altered lymphocyte catecholamine reactivity in mice subjected to chronic mild stress
Biochem. Pharmacol.
(2003) - et al.
Continuous in vivo treatment with catecholamines suppresses in vitro reactivity of rat peripheral blood T lymphocytes via alpha-mediated mechanisms
J. Neuroimmunol.
(1992) - et al.
Adrenergic suppression of peripheral blood T cell reactivity in the rat is due to activation of peripheral alpha 2-receptors
J. Neuroimmunol.
(1995) - et al.
Beta-blockade enhances adrenergic immunosuppression in rats via inhibition of melatonin release
J. Neuroimmunol.
(1996) - et al.
Chemokines: multiple levels of leukocyte migration control
Trends Immunol.
(2004) - et al.
Prolonged isoproterenol treatment alters immunoregulatory cell traffic and function in the rat
Brain Behav. Immun.
(1993) - et al.
The parasympathetic nervous system takes part in the immuno-neuroendocrine dialogue
J. Neuroimmunol.
(1991) - et al.
Noradrenaline induces phosphorylation of ERK-2 in human peripheral blood mononuclear cells after induction of alpha(1)-adrenergic receptors
J. Neuroimmunol.
(2000)
Norepinephrine, the beta-Adrenergic Receptor, and Immunity
Brain Behav. Immun.
Adaptive immunity in mice lacking the beta(2)-adrenergic receptor
Brain Behav. Immun.
Cited by (13)
Response of Hematopoietic Stem and Progenitor Cells to Reserpine in C57Bl/6 Mice
2016, Bulletin of Experimental Biology and MedicineThe role of catecholamines in stem cell mobilisation
2016, Issues in ToxicologyMarrow Microenvironment and Biology of Mobilization of Stem Cells
2016, Thomas' Hematopoietic Cell Transplantation: Fifth EditionNorepinephrine attenuates CXCR4 expression and the corresponding invasion of MDA-MB-231 breast cancer cells via β2-adrenergic receptors
2015, European Review for Medical and Pharmacological Sciences