1. ¹Department of Medical Physiology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
2. ²Institute of Pharmacology and Neurosciences, Faculty of Medicine, University of Lisbon, Lisbon, Portugal
3. ³Institute of Molecular Medicine, University of Lisbon, Lisbon, Portugal
4. ⁴Department of Molecular Neurobiology, University of Groningen, Groningen, The Netherlands
5. ⁵Leiden/Amsterdam Center for Drug Research, Gorlaeus Laboratories, Leiden, The Netherlands

Correspondence: Dr K Biber, Department of Medical Physiology, University Medical Center Groningen, University of Groningen, Ant. Deusinglaan 1, Groningen 9713 AV, The Netherlands. Tel: +31 50 3632706; Fax: +31 50 3632751; E-mail: k.p.h.biber@med.umcg.nl

⁶These authors contributed equally to this study.

Received 18 December 2006; Revised 18 September 2007; Accepted 29 September 2007; Published online 7 November 2007.

Abstract

The immunological response in the brain is crucial to overcome neuropathological events. Some inflammatory mediators, such as the immunoregulatory cytokine interleukin-6 (IL-6) affect neuromodulation and may also play protective roles against various noxious conditions. However, the fundamental mechanisms underlying the long-term effects of IL-6 in the brain remain unclear. We now report that IL-6 increases the expression and function of the neuronal adenosine A₁ receptor, with relevant consequences to synaptic transmission and neuroprotection. IL-6-induced amplification of A₁ receptor function enhances the responses to readily released adenosine during hypoxia, enables neuronal rescue from glutamate-induced death, and protects animals from chemically induced convulsing seizures. Taken together, these results suggest that IL-6 minimizes the consequences of excitotoxic episodes on brain function through the enhancement of endogenous adenosinergic signaling.