The existence of immune-neuro-endocrine interactions is supported by
abundant evidence showing that immune cytokines can affect
neuro-endocrine mechanisms, and that hormones, neurotransmitters, and
neuropeptides can, in turn, influence immune functions. Indeed,
activation of the immune system by innocuous antigens results in
changes in the activity of discrete populations of brain neurons, and
in several neuro-endocrine mechanisms involved in immunoregulation.
Cytokines synthesized by brain cells could actively contribute to
these interactions if their production would be triggered by both
peripheral immune signals and central neuronal signals. We have
studied this possibility using as models the stimulation of peripheral
immune cells by the endotoxin LPS, and the stimulation of hippocampal
neurons during long-term potentiation (LTP) of synaptic activity.
Administration of a low dose of LPS, which does not disrupt the blood
brain barrier and that does not cause an endotoxic shock, induced
IL-1b, IL-6, TNFb and IFNg gene expression in the brain. Increased
accumulation of IL-1 and IL-6 mRNA transcripts was preferentially
detected in the hypothalamus and hippocampus, while TNFa and IFNg gene
expression was more marked in the thalamus-striatum. There was nearly
no cytokine induction in the brain cortex and no preferential
expression of these messengers in circumventricular organs.
During LTP, a process considered to underlie certain forms of learning
and memory, IL-1b and IL-6, but no TNFa, gene expression was
substantially increased. This increase, which was detected both in
vivo and in vitro, was long lasting, specific to potentiation, and
could be prevented by blockade of NMDA-glutamate receptors.
Furthermore, blockade of IL-1 receptors by the specific natural
interleukin-1 receptor antagonist (IL-1ra) resulted in a reversible
impairment of LTP maintenance without affecting its induction.
These results show that cytokine production in the brain can be
induced by both peripheral immune and central neuronal signals. This
dual control of cytokine production lead us to propose that
interactions between cytokine-producing cells (glia and/or neurons)
and stimulated neurons constitute a relevant step in CNS-immune system
communication. |
