Neurotoxic consequences of central long-term administration of interleukin-2 in rats

Interleukin-2 is an immunoregulatory cytokine with several recently established CNS activities. Central effects of interleukin-2 include growth promotion for neuronal and glial cells as well as modulatory influences on neurotransmission and hormone release. However, little is known about the consequences in the CNS of chronically elevated levels of interleukin-2. Alterations in the interleukin-2/interleukin-2 receptor system are not only associated with CNS trauma, inflammation and certain neuropathologies; elevated interleukin-2 concentrations are especially induced during the therapeutic use of interleukin-2 in cancer treatments. In the present study, intracerebroventricular (i.c.v.) interleukin-2 infusions (5 15 U/h) were performed in Sprague Dawley rats for up to 14 days. Interleukin-2-treated animals showed significantly increased plasma levels of corticosterone indicating an hyperfunctioning of the hypothalamic-pituitary-adrenocortical axis that lasted over the 14 day 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 the binding levels of cholinergic M1 and M2 as well as dopaminergic D1 and D2 receptors in selected brain areas in which interleukin-2 was shown to modulate neurotransmission and which are enriched with interleukin-2 receptor expression. Decreased receptor binding levels were observed in the frontoparietal cortex (M2, D1, D2), hippocampal CA1 region (M1, M2) and the nucleus accumbens (D2). Histological and immunohistochemical examination of the brains of interleukin-2-treated animals revealed multiple alterations. Interleukin-2 treatment resulted in an intracranial accumulation of non-neural, MHC class II-positive cells as well as T and B lymphocytes within the infused brain hemisphere. Cellular infiltrates were associated with angiogenesis and the deposition of extracellular matrix material, such as fibronectin. Adjacent brain regions that were partly invaded and dislodged by the cellular masses were characterized by reactive astrogliosis, microglial activation, endothelial upregulation of adhesion molecules, myelin damage and neuronal loss. Together the data suggest that persistently elevated central levels of interleukin-2 can interfere with several CNS functions and may lead to nervous tissue injury. These findings could be relevant to CNS pathologies characterized by abnormal interleukin-2 production and to central responses to interleukin-2 treatments.