In a previous study we demonstrated that mice pretreated with the highly selective
α2-adrenoceptor antagonist CH-38083 showed blunting of the tumor necrosis factor-α
(TNF-α) response induced by bacterial lipopolysaccharide (LPS). In the present study,
the effect of a selective block of α2-adrenoreceptor and the role of the sympathetic
nervous system (SNS) in the regulation of LPS-induced TNF-α production was explored
further using different selective adrenoceptor antagonists and agonists. While adrenalectomy
did not prevent the effect of CH-38083, the block of the sympathetic transmission
by chlorisondamine fully abolished the inhibitory effect of CH-38083 on LPS-induced
TNF-α production, suggesting that the effect of the α2-adrenoceptor blocking agent
is corticosteroid-independent, but it requires intact sympathetic activity. Since
the selective block of α2-adrenoceptors results in an increased sympathetic activity
and an increase of the release of noradrenaline (NA) in both the central and the peripheral
nervous systems, and in our experiments propranolol, a non-selective β-adrenoceptor
antagonist, and atenolol, a selective antagonist of β1-adrenoceptors, prevented the
effect of α2-adrenoceptor blockade by CH-38083 of the TNF-α response induced by LPS,
it seems likely that the excessive stimulation by NA of β1-adrenoceptors is responsible
for this action. The role of β-adrenoceptors and endogenous catecholamines is further
substantiated by the finding that pretreatment of animals with propranolol alone resulted
in a dose-dependent increase of the TNF-α response induced by LPS, and that isoproterenol,
a non-selective β-adrenoceptor agonist, decreased it. Additionally, it was shown that
prazosin, an α1-and α2B-adrenoceptor antagonist, reduced LPS-induced TNF-α production.
However, l-phenylephrine, a selective α1-adrenoceptor agonist, was not able to modulate
the TNF-α response following LPS challenge. Our findings that α2-and β-adrenoceptor
antagonists are able to decrease or increase, respectively, the TNF-α response elicited
by LPS indicate that SNS, through release of endogenous catecholamines, is involved
in vivo in the regulation of LPS-induced TNF-α production. In this process, the β-adrenoceptor-mediated
events seems to play a pivotal role. Since the blockade of sympathetic activity by
chlorisondamine failed to affect LPS-induced TNF-α release, it seems likely that,
in vivo, the inhibitory effect of SNS on TNF-α production, mediated via β-adrenoceptors,
is opposed by an effect of catecholamines on α2-adrenoceptors. It is suggested that
the fine-tuning of TNF-α release exerted by SNS in vivo might be particularly important
during immunological and non-immunological stress, when the concentration of catecholamines
is increased in the close proximity of TNF-α-secreting cells, which are known to possess
adrenoceptors.
