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Neurotoxicity induced by interleukin-2: involvement of infiltrating immune cells
U K Hanisch1, J Neuhaus, R Quirion
1Max Delbrück Centre for Molecular Medicine, Department of Cellular Neurobiology, Berlin-Buch, Germany.
Insights
Chronic central Interleukin-2 (IL-2) administration causes neurotoxicity in rats, leading to brain tissue damage, immune cell invasion, and myelin destruction. These findings highlight IL-2
Area of Science:
- Neuroimmunology
- Neuroscience
- Immunology
Background:
- Interleukin-2 (IL-2) is a critical immune regulator with known effects on neural cells.
- Previous research indicated neurotoxicity from chronically elevated central nervous system (CNS) IL-2 levels.
- Neuroimmune interactions are crucial for understanding brain function and disease.
Purpose of the Study:
- To detail the brain tissue architecture modifications resulting from chronic, low-dose IL-2 administration in the CNS.
- To investigate the cellular and molecular mechanisms underlying IL-2-induced neurotoxicity.
Main Methods:
- Intracerebroventricular (i.c.v.) administration of IL-2 (5 and 15 U/h) to Sprague-Dawley rats for up to 14 days using osmotic minipumps.
- Histological examination of brain tissue to assess structural changes and cellular infiltrates.
- Immunocytochemistry to identify cell types, antibody presence, and glial/neuronal interactions.
Main Results:
- Massive cellular infiltrates, angiogenesis, and extracellular matrix changes were observed in the ipsilateral hemisphere.
- Chronic IL-2 central administration led to T and B lymphocyte invasion and accumulation of MHC class II-positive cells.
- Myelin destruction and neuronal cell loss were evident in regions surrounding IL-2-induced infiltrates.
Conclusions:
- Chronically elevated CNS IL-2 levels induce significant neuroinflammation and tissue damage, including demyelination and neuronal loss.
- IL-2 disrupts brain tissue homeostasis, impacting neurotransmission, endocrine functions, and potentially contributing to CNS disorders.
- Findings are relevant to understanding brain injuries and CNS disorders associated with elevated IL-2 or immune involvement.
Abstract:
Interleukin-2 (IL-2), a key regulator of immune functions, also has potent effects on neurons and glia. IL-2 modulates neural cell growth and survival and transmitter and hormone releases and is thought to mediate neuroimmune interactions. Investigating the neuroendocrine consequences of chronically elevated central nervous system (CNS) levels of IL-2, we recently observed marked neurotoxicity [Hanisch et al. (1994) Endocrinology 135:2465-2472]. In the present study, we characterize in detail the modifications in brain tissue architecture as they result in Sprague-Dawley rats from intracerebroventricular (i.c.v.) administration of low amounts of IL-2 (5 and 15 U/h, respectively, delivered by means of osmotic minipumps for up to 14 days). Histological inspection of the brains revealed massive cellular infiltrates in the ipsilateral hemisphere. The infiltrates were associated with pronounced angiogenesis and changes in the composition of the extracellular matrix. These anatomical changes apparently developed between day 7 and 14. They were specific for IL-2 and were not seen in animals treated, for example, with heat-inactivated IL-2 (controls). We further show that chronic central administration of IL-2 let to T and B lymphocyte invasion of the brain and an intracranial agglomeration of large numbers of MHC class II-positive cells. Immunocytochemistry revealed a widespread inundation of CNS tissue and a decoration of glial cells and neurons by endogenous antibodies. Tissue regions around the IL-2-induced infiltrates showed myelin destruction and neuronal cell loss. Chronically elevated CNS levels of IL-2 may, thus, not only interfere with neurotransmission and endocrine functions but also severely disturb tissue homeostasis. Therefore, the present findings could be relevant to brain injuries, CNS disorders, and clinical treatments associated with increased IL-2 levels or involving an immune component.