Adrenergic/Cholinergic Immunomodulation in the Rat Model—In Vivo Veritas?
Adrenergic/Cholinergic Immunomodulation in the Rat Model -In Vivo Veritas?
I. RINNERa 0
P. FELSNERa 0
P.M. LIEBMANN 0
D. HOFER 0
A. WOLFLERa 0
A. GLOBERSON 0
K. SCHAUENSTEIN 0
0 alnstitute of General and Experimental Pathology, University of Graz, Austria; bDepartment of Immunology, Weizmann Institute of Science , Rehovot , Israel
For several years, our group has been studying the in vivo role of adrenergic and cholinergic mechanisms in the immune-neuroendocrine dialogue in the rat model. The main results of these studies can be summarized as follows: (1) exogenous or endogenous catecholamines suppress PBL functions through alpha-2-receptor-mediated mechanisms, lymphocytes of the spleen are resistant to adrenergic in vivo stimulation, (2) direct or indirect cholinergic treatment leads to enhanced ex vivo functions of splenic and thymic lymphocytes leaving PBL unaffected, (3) cholinergic pathways play a critical role in the "talking back" of the immune system to the brain, (4) acetylcholine inhibits apoptosis of thymocytes possibly via direct effects on thymic epithelial cells, and may thereby influence T-cell maturation, (5) lymphocytes of the various immunological compartments were found to be equipped with the key enzymes for the synthesis of both acetylcholine and norepinephrine, and to secrete these neurotransmitters in culture supernatants Chelmicka-Schorr and Arnason, 1990). Central and *Corresponding author.
Neuroimmunomodulation; catecholamines; acetylcholine; lymphocytes; thymic epithelial cells; apoptosis; choline-acetyl transferase; dopamine-beta-hydroxylase
INTRODUCTION
Investigations in the past decades have unraveled
terminals forming "synapsislike" contacts to the
immune cells
(Bulloch and Moore, 1981; Felten et al.,
1987)
. Inversely, T lymphocytes were found to
close mutual relationships between the
neuroendoregularly invade the central nervous system at random
crine and the immune systems (
Cotman et al., 1987
;
(Hickey et al., 1991)
. A great variety of common
receptors,
surface
proteins,
and
mediators
are
peripheral lymphoid organs are innervated by the
expressed at high levels in both the neuroendocrine
sympathetic and parasympathetic systems with nerve
and the immune
systems providing information
exchange within as well as between the systems.
Adrenergic, muscarinic, and nicotinic cholinergic,
and many peptidergic receptors have been identified
on lymphocytes
(Plaut, 1987)
. Activation of these
receptors can exert immunosuppressive or enhancing
effects, depending on the respective signal molecule,
the type of immune cell concerned
(Blalock, 1989)
,
and the different microenvironments of lymphoid
tissues
(Felsner et al., 1992; Rinner and Schauenstein,
1991; Rinner et al., 1992)
. The generation of
neurohormones, neuropeptides, and neurotransmitters by
thymocytes and peripheral lymphocytes has been
documented in several species
(Smith et al., 1990;
Rinner and Schauenstein, 1993)
, and, on the other
hand, neural and endocrine tissues are known to
express lymphokines and monokines as well as high
densities of their membrane receptors
(Velasco et al.,
1991; Cunningham and Souza, 1993)
. Functionally,
cytokines influence endocrine and central nervous
functions, including activation of the
hypothalamicpituitary adrenal and hypothalamic-godanal axes,
induction of fever or slow wave sleep, and signaling
to the structures of the "limbic system" (Haas and
Schauenstein, 1997).
Our group is interested in defining the role of the
autonomous nervous system within the dialogue
between the central nervous system and the immune
system. In the rat model, we could show that the in
vivo treatment with adrenergic and cholinergic
agonists had pronounced and partly opposite effects on ex
vivo functions of lymphocytes
(Rinner and
Schauenstein, 1991; Felsner et al., 1992, 1995)
, and that the
cholinergic system particularly takes part in the
signaling from the peripheral immune system to the
brain
(Rinner and Schauenstein, 1991)
.
ALPHA-ADRENERGIC SUPPRESSION OF
PBL PROLIFERATIVE RESPONSE IN THE
RAT MODEL
The literature data on adrenergic immunoregulation
are conflicting; both suppression and enhancement
have been reported as a consequence of alpha- or
beta-adrenergic stimulation
(Hadden et al., 1970;
Pearlman, 1971; De Pelchin and Letesson, 1981;
Felten et al., 1987; Felten and Felten, 1994; Madden
et al., 1995)
. These differences are probably due to
differences in the experimental approach, such as, for
example, in vivo versus in vitro studies, species
differences, and epiphenomena due to "handling
stress" of laboratory animals
(Rinner et. al., 1992)
.
In our own studies, we tried to define the in vivo
effects of chronically enhanced levels of peripheral
catecholamines on ex vivo functions of lymphocytes
of rats. The experimental model consists of s.c.
implantation of retard tablets that provide a controlled
release of adrenergic agonists or antagonists during
24 hr. The resul (...truncated)