IL-1␤ and its endogenous receptor antagonist (IL-1RaIL-1␤ appears to be involved in neuronal network excitability because it affects the turnover and release of various neurotransmitters (1) and the expression of neuropeptides and neurotrophic factors (3-5) and alters synaptic transmission and ionic currents (6-9) in several rodent forebrain regions.Convulsant stimuli increase the production of IL-1␤, its naturally occurring receptor antagonist (IL-1Ra), and IL-1R type I and II predominantly in glia in rodent central nervous system within hours of seizure induction (10-15).We recently showed that IL-1␤ prolongs hippocampal electroencephalographic (EEG) seizures in a N-methyl-D-aspartate receptor-dependent manner, and this action was blocked by .In this study, we investigated whether IL-1Ra has anticonvulsant properties in rodents. We found that intracerebral application of recombinant IL-1Ra or its endogenous overexpression in astrocytes potently inhibited behavioral and EEG seizures induced by bicuculline methiodide in mice. This effect was mediated specifically by IL-1R type I, because IL-1Ra was ineffective in knockout mice deficient in these receptors.Thus, the functional interaction between brain-born IL-1␤ and IL-1Ra during seizures, (i) may play a critical role in the physiopathological functions of IL-1␤, and (ii) may significantly affect the maintenance and spread of seizures. Materials and MethodsAnimals. Procedures involving animals and their care were conducted in conformity with institutional guidelines in compliance with national and international laws and policies (4D. L. N. 116, Gazzetta Ufficiale, supplement 40, 18-2-1992 and European

The acute inflammatory response following traumatic brain injury (TBI) has been shown to play an important role in the development of secondary tissue damage. The proinflammatory cytokines interleukin-1 (IL-1) and tumor necrosis factor-alpha (TNFalpha), are induced early after brain injury and have been implicated in the delayed damage. The IL-1 receptor antagonist (IL-1ra) has been shown to modulate the proinflammatory cytokine cascade by blocking the binding of IL-1 to its signaling receptor. In this study, we investigated the effect of transgenic overexpression of IL-1ra on the cytokine expression and neurological damage in a closed head injury (CHI) model of TBI. The neurological recovery, as analyzed by neurological severity score (NSS), was significantly higher in transgenic mice overexpressing the human secreted form of IL-1ra in astrocytes, directed by the murine glial fibrillary acidic protein promoter, as compared to wild-type mice. Analysis of tissue levels of cytokines by ELISA showed increased levels of TNFalpha in the cerebral cortex from the wild type mice 1 h after injury. After 4 h significant increases in the levels of IL-1beta and IL-6 were observed in the wild type mice. In the transgenic mice, on the other hand, no effect on TNFalpha levels was observed and no significant increases in IL-1beta and IL-6 levels could be detected until 6 h after injury. Thus, it can be concluded that blockage of IL-1 signaling by elevated levels of IL-1ra has a neuroprotective effect, in agreement with previous reports, and that central overexpression of IL-1ra results in delayed proinflammatory cytokine induction and improved neurological recovery after traumatic brain injury.

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Proteins of the interleukin-1 (IL-1) system include the secreted agonist IL-1beta, and the receptor antagonist IL-1ra, both competing for binding to the IL-1 receptor (IL-1R). IL-1beta and IL-1ra are highly inducible under different forms of stress, such as excitatory neurotransmitter excess occurring during seizures, in infection and inflammation, and during neurotrauma. In each of these conditions induction of IL-1beta precedes that of IL-1ra, resulting in up to 10-20-fold elevation of IL-1beta concentrations. Consequently, IL-1beta induces the elevation of other proinflammatory molecules, including IL-6, IL-1R1, COX2, and iNOS, as well as of IL-1ra. Elevation of IL-1ra is of key importance for quenching the inflammatory response at the IL-1R1 as part of an autoregulatory loop. In seizures, IL-1ra is a strong anticonvulsant and in IL-1beta-dependent fever, a powerful antipyretic. In traumatic brain injury (TBI), the ability of patients to mount an IL-1ra response, as measured in the CSF, strongly correlated with the neurological outcome. Selective induction or pharmacological application of IL-1ra may be sparing neurons in seizures and neurotrauma.