Interleukin-1 receptor antagonist exerts agonist activity in the hippocampus independent of the interleukin-1 type I receptor

Interleukin-1 receptor antagonist (IL-1RA) selectively and competitively inhibits the actions of IL-1 at its receptors and has not been reported to have agonist activity. This study demonstrates that stimulation of synaptosomes with IL-1RA in vitro, mimicked the effects of IL-1 beta by decreasing glutamate release and increasing JNK phosphorylation. These effects of IL-1RA, but not IL-1 beta, were maintained in IL-1 type I receptor (IL-1RI) defective mice. IL-1 beta blocked these IL-1ra-induced effects suggesting that it may also act independently of IL-1RI in some circumstances. Furthermore, IL-1RA mimicked the inhibitory effect of IL-1 beta on long-term potentiation (LTP) in the hippocampus. These data, taken together with our findings that IL-1RA binds to hippocampal synaptosomes in the absence of IL-1RI, provide evidence that IL-1RA exerts agonist activity in the hippocampus independent of IL-1RI.