IMMUNE AND NEURAL CONTROL OF BRAIN CYTOKINES
H.O. Besedovsky, F. Pitossi, H. Schneider, D. Balschun, A. del
Rey
Dep. of Physiology, Philipps Marburg University,
Germany
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.