Interleukin-1 receptors and ligands in the nervous system

The functional interaction between the immune (IS) and the central nervous systems (CNS) is suggested by the fact that these systems are sharing mediators and receptors. Interleukin-1 (IL-1) alpha, beta and IL1 receptor antagonist (IL-1ra) are powerful regulators of both systems and specific receptors (Type I and II) have been characterized in the nervous tissue by autoradiographic and molecular biology techniques. Stimulation of the immune system by intraperitoneal injection of LPS induced a marked increase in IL-1 alpha, beta, ra, mRNA in the brain and in the spleen. Receptors type I and II mRNAs are also increased in both tissues. However, free brain IL-1 receptor levels are decreased (down-regulation) while they are unaffected in pituitary and spleen, indicating the autonomy of brain functioning. This sharp decline in free receptors in the brain compartment is interpreted as occupancy/down-regulation by high endogenous concentrations of IL-1s. Similar effects are obtained following rabies virus infection, leading to an increase in brain IL-1 synthesis and receptor down-regulation specific to the brain. Stress and glucocorticoid treatments are strong inhibitors of immune functions by inhibiting IL1 synthesis. The effect of stress and dexamethasone (Dex) on the density of IL-1 receptors in the brain and pituitary was, therefore, investigated before or after LPS stimulation. In contrast with what is observed in the pituitary and in the immune system, these treatments did not modify brain IL-1 receptors indicating a lack of sensitivity of the brain IL-1 system to glucocorticoids. In a strain of autoimmune mice (NZB), striking abnormalities in IL-1 receptors expression are detectable in the neuronal tissues (dentate gyrus) while vascular tissues seem to be normal. The relationship between this defect and the accumulation of autoantibodies remains to be clarified. However, this is in accordance with the immunosuppressive effect of IL-1 injection into the brain by stimulation of autonomic and neuroendocrine HPA (stress axis) pathways and with the hypothesis that neuronal IL-1 receptors are the origin of inhibitory signals towards the peripheral immune system. In the absence of these regulatory signals, the immune system could be over-reactive in NZB mice. In conclusion brain structures express IL-1 and IL-1 receptors which seem to be quite independent of their counterpart, present in the immune system during infectious episodes. This confirms the important role of IL-1 in the CNS as a neuro-modulator and as a regulator of peripheral immune functions.