Metallothioneins (MTs) are a family of proteins which in mammals is comprised of four isoforms (MT-I-IV). MT-I and MT-II are expressed in many tissues, whereas MT-III is expressed exclusively in the central nervous system (CNS). In contrast to the liver, the knowledge of the regulation of the different MT isoforms in the brain is scarce. A number of cytokines have been shown to be important regulators of MT synthesis in vivo and in vitro. In accordance with this concept, the i.p. administration of endotoxin, which elicits the release of cytokines not only in peripheral tissues but also in the brain, caused an overall increase of MT-I + II levels in the rat brain which was very significant in medulla + pons and cerebellum. Among the putative cytokines involved in endotoxin-elicited brain MT-I + II induction, interleukin-1 (IL-1) and interleukin-6 (IL-6) are likely candidates. These cytokines have a variety of effects in the brain, and they are major regulators of MT-I + II synthesis in tissues such as the liver. Here we show the administration of IL-1 and IL-6 into the third ventricle increased MT-I + II protein levels in specific brain areas in the rat. IL-1 tended to increase MT-I + II levels in all brain areas studied, but significantly in the striatum, hypothalamus, medulla + pons and cerebellum. The effect of IL-6 was more restricted, but a significant increase of MT-I + II levels was still observed in frontal cortex, hypothalamus and cerebellum. The results suggest that IL-1 and IL-6 are important regulators of brain MT-I + II and that these cytokines could mediate MT-I + II induction after an immunological insult.