Abstract

Interleukin-1β (IL-1β), a polypeptide immune mediator, is induced within the central nervous system in response to a variety of pathological stimuli, including systemic infection, hypoxia, brain trauma, and seizure. IL-1β action on the γ-aminobutyric acid type A (GABA_A) inhibitory neurotransmitter receptor was investigated in whole cell patch-clamped cultured hippocampal neurons. Application of IL-1β at concentrations encountered in pathophysiological conditions (1–10 ng/ml; 59–590 pM) irreversibly decreased the peak magnitude of current elicited by 30 μM GABA. Current inhibition was IL-1β concentration- and time-dependent and was prevented by a specific IL-1β type I receptor antagonist. No significant changes in current kinetics or reversal potential were observed. The IL-1β depression of GABA current was inhibited by high concentrations of nonspecific kinase inhibitors staurosporine (500 nM) and 1-(5-isoquinolinyl-sulfonyl)-2-methylpiperazine (H-7; 50 μM), but not by a protein kinase C selective inhibitor calphostin C (5 μM). We conclude that IL-1β inhibits GABA_A receptor function in hippocampal neurons by the involvement of an unidentified kinase. This blockade of the GABA_A inhibitory neurotransmitter receptor may underlie the central nervous system hyperexcitability seen in many pathophysiological conditions.