INTERLEUKIN-6 AND TUMOR-NECROSIS-FACTOR-ALPHA TYPE-1 RECEPTOR-DEFICIENT MICE REVEAL A ROLE OF IL-6 AND TNF-ALPHA ON BRAIN METALLOTHIONEIN-IAND METALLOTHIONEIN-III REGULATION

Metallothioneins (MTs) are a family of low molecular weight proteins w hich in rodents is comprised of several isoforms (MT-I to MT-IV). MT-I and MT-II are widely expressed isoforms, whereas MT-III is mainly exp ressed in the central nervous system and is the only isoform that inhi bits survival and neurite formation of rat cortical neurons in vitro. However, the physiological roles and regulation of these proteins in t he brain are poorly characterized. In this report we have studied the putative role of IL-6 and TNF-alpha on the regulation of brain MT-I an d MT-III, by using mice carrying a null mutation in the IL-6 or the TN F-alpha type 1 receptor genes or both. In situ hybridization analysis revealed that brain MT-I induction by bacterial lipopolysaccharide (LP S) was significantly lower in IL-6- and TNFR1-deficient mice, and to a greater extent in the double mutant mice, in most brain areas studied . These results suggest that the MT-I isoform could be considered an a cute-phase protein in the brain, which is consistent with previous stu dies in transgenic mice overexpressing IL-6 in astrocytes. In contrast to LPS, brain MT-I induction by restraint stress was not affected sig nificantly by IL-6 or TNFR1 deficiencies, suggesting that these cytoki nes are not important during the stress response in the brain. In basa l conditions, it was also observed that the double mutant mice had dim inished MT-I mRNA levels in several brain areas. In contrast to MT-I, MT-III mRNA levels were minimally affected by either LPS or stress. Ye t, significant decreasing effects of IL-6 and TNFR1 deficiencies were observed in the Purkinje neuronal layer of the cerebellum (after LPS) and ependymal cells (after LPS and stress). In contrast, significant i ncreasing effects, especially of TNFR1 deficiency, were observed in CA 1 hippocampal area, retrosplenial and parietal cortex, and in thalamic nuclei (after LPS). These results demonstrate that IL-6 and TNF-alpha are involved in brain MTs regulation during LPS-elicited inflammatory response but not during the stress response. (C) 1998 Elsevier Scienc e B.V. All rights reserved.