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The Journal of Neuroscience, September 24, 2003, 23(25):8692-8700

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Cellular/Molecular
Interleukin-1 Enhances NMDA Receptor-Mediated Intracellular Calcium Increase through Activation of the Src Family of Kinases

B. Viviani,^1,2 S. Bartesaghi,^1,2 F. Gardoni,² A. Vezzani,³ M. M. Behrens,⁴ T. Bartfai,⁴ M. Binaglia,¹ E. Corsini,^1,2 M. Di Luca,² C. L. Galli,¹ and M. Marinovich^1,2

¹Laboratory of Toxicology and ²Center of Excellence on Neurodegenerative Diseases, Department of Pharmacological Sciences, University of Milan, 20133 Milan, Italy, ³Department of Neuroscience, Mario Negri Institute for Pharmacological Research, 20157 Milan, Italy, and ⁴The Harold L. Dorris Neurological Research Center, Department of Neuropharmacology, The Scripps Research Institute, La Jolla, California 92037

Interleukin (IL)-1 is a proinflammatory cytokine implicated in various pathophysiological conditions of the CNS involving NMDA receptor activation. Circumstantial evidence suggests that IL-1 and NMDA receptors can functionally interact. Using primary cultures of rat hippocampal neurons, we investigated whether IL-1 affects NMDA receptor function(s) by studying (1) NMDA receptor-induced [Ca²⁺]_i increase and (2) NMDA-mediated neurotoxicity. IL1 (0.01-0.1 ng/ml) dose-dependently enhances NMDA-induced [Ca²⁺]_i increases with a maximal effect of 45%. This effect occurred only when neurons were pretreated with IL-1, whereas it was absent if IL-1 and NMDA were applied simultaneously, and it was abolished by IL-1 receptor antagonist (50 ng/ml). Facilitation of NMDA-induced [Ca²⁺]_i increase by IL-1 was prevented by both lavendustin (LAV) A (500 nM) and 4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine (PP2) (1 µM), suggesting an involvement of tyrosine kinases. Increased tyrosine phosphorylation of NMDA receptor subunits 2A and 2B and coimmunoprecipitation of activated Src tyrosine kinase with these subunits was observed after exposure of hippocampal neurons to 0.05 ng/ml IL-1. Finally, 0.05 ng/ml IL-1 increased by 30% neuronal cell death induced by NMDA, and this effect was blocked by both lavendustin A and PP2.

These data suggest that IL-1 increases NMDA receptor function through activation of tyrosine kinases and subsequent NR2A/B subunit phosphorylation. These effects may contribute to glutamate-mediated neurodegeneration.

Key words: cytokines; tyrosine kinase; excitotoxicity; IL-1 receptor type I; NR2A/B subunits; hippocampal neurons

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Received June 23, 2003; revised July 30, 2003; accepted August 1, 2003.

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