REACTIVE GLIOSIS AS A CONSEQUENCE OF INTERLEUKIN-6 EXPRESSION IN THE BRAIN - STUDIES IN TRANSGENIC MICE

Gliosis is a characteristic pathologic state in many CNS disorders. Cy tokines are considered to be effecters of gliosis. In order to explore the role of IL-6 in gliosis, the temporal and spatial expression of t he IL-6 gene and its consequent effects on the brain were studied in a GFAP-IL6 transgenic mouse model. In GFAP-IL6 mice, IL-6 transgene exp ression was detectable in the brain at 1 week postnatally and increase d to maximal levels by 3 months of age before declining at 8 and 12 mo nths. Enhanced glial fibrillary acidic protein (GFAP) (marker for astr ocytes) and Mac-I (marker for microglia) mRNA expression were first pr ominent at 1 month, increased to maximum levels by 3 months and remain ed significantly elevated through 12 months of age. Western blot analy sis revealed that the enhanced GFAP mRNA expression in these transgeni c mice was accompanied by increased GFAP protein levels. Immunostainin g for Mac-I demonstrated that in addition to an increased staining int ensity, the number of cells expressing the microglial/macrophage marke r was also apparently increased, particularly in the cerebellum and br ain stem. Concurrent with IL-6 transgene mRNA expression and reactive gliosis, upregulation of LL-1 alpha/beta, TNF alpha, ICAM-1 and EB22/5 .3 (acute-phase reactant) but not inducible nitric oxide synthase gene expression was also observed. EB22/5.3 mRNA expression was most promi nent and increased progressively with age. Expression of the IL-6, GFA P and EB22/5.3 RNAs was found to have similar distribution in the brai n being found predominantly in the cerebellum, brain stem and sub-cort ical regions. In conclusion, the constitutive expression of IL-6 in th e brain induced the development of a pronounced and lifelong reactive gliosis affecting both astrocytes and microglia. The altered state of these cells may contribute to the functional and structural CNS impair ment exhibited by the GFAP-IL6 mice. Finally, in these mice, expressio n of the EB22/5.3 gene correlated closely with the progression of neur opathy indicating that this acute-phase response gene was a good marke r for and may be involved in the pathogenesis of CNS injury mediated b y the expression of IL-6.