NEUROTOXIC CONSEQUENCES OF CENTRAL LONG-TERM ADMINISTRATION OF INTERLEUKIN-2 IN RATS

Interleukin-2 is an immunoregulatory cytokine with several recently es tablished CNS activities. Central effects of interleukin-2 include gro wth promotion for neuronal and glial cells as well as modulatory influ ences on neurotransmission and hormone release. However, little is kno wn about the consequences in the CNS of chronically elevated levels of interleukin-2. Alterations in the interleukin-2. interleukin-2 recept or system are not only associated with CNS trauma, inflammation and ce rtain neuropathologies; elevated interleukin-2 concentrations are espe cially induced during the therapeutic use of interleukin-a in cancer t reatments. In the present study, intracerebroventricular (i.c.v.) inte rleukin-2 infusions (5-15 U/h) were performed in Sprague-Dawley rats f or up to 14 days. Interleukin-2-treated animals showed significantly i ncreased plasma levels of corticosterone indicating an hyperfunctionin g of the hypothalamic-pituitary-adrenocortical axis that lasted over t he 14 dap infusion period. Moreover, the performance of interleukin-2- treated animals in the Morris swim maze task was transiently impaired. Quantitative receptor autoradiographic analyses revealed changes in t he binding levels of cholinergic M-1 and M-2 as well as dopaminergic D -1 and D-2 receptors in selected brain areas in which interleukin-2 wa s shown to modulate neurotransmission and which are enriched with inte rleukin-2 receptor expression. Decreased receptor binding levels were observed in the frontoparietal cortex (M-2, D-1, D-2), hippocampal CA1 region (M-1, M-2) and the nucleus accumbens (D-2). Histological and i mmunohistochemical examination of the brains of interleukin-2-treated animals revealed multiple alterations. Interleukin-2 treatment resulte d in an intracranial accumulation of non-neural, MHC class II-positive cells as well as T and B lymphocytes within the infused brain hemisph ere. Cellular infiltrates were associated with angiogenesis and the de position of extracellular matrix material, such as fibronectin. Adjace nt brain regions that were partly invaded and dislodged by the cellula r masses were characterized by reactive astrogliosis, microglial activ ation, endothelial upregulation of adhesion molecules, myelin damage a nd neuronal loss. Together the data suggest that persistently elevated central levels of interleukin-2 can interfere with several CNS functi ons and may lead to nervous tissue injury. These findings could be rel evant to CNS pathologies characterized by abnormal interleukin-2 produ ction and to central responses to interleukin-2 treatments. (C) 1997 I BRO. Published by Elsevier Science Ltd.