Neurologic disease induced in transgenic mice by cerebral overexpression of interleukin 6.

Abstract

Cytokines are thought to be important mediators in physiologic and pathophysiologic processes affecting the central nervous system (CNS). To explore this hypothesis, transgenic mice were generated in which the cytokine interleukin 6 (IL-6), under the regulatory control of the glial fibrillary acidic protein gene promoter, was overexpressed in the CNS. A number of transgenic founder mice and their offspring exhibited a neurologic syndrome the severity of which correlated with the levels of cerebral IL-6 expression. Transgenic mice with high levels of IL-6 expression developed severe neurologic disease characterized by runting, tremor, ataxia, and seizure. Neuropathologic manifestations included neurodegeneration, astrocytosis, angiogenesis, and induction of acute-phase-protein production. These rmdings indicate that cytokines such as IL-6 can have a direct pathogenic role in inflammatory, infectious, and neurodegenerative CNS diseases.

Interleukin‐6 induces transcriptional activation of vascular endothelial growth factor (VEGF) in astrocytes in vivo and regulates VEGF promoter activity in glioblastoma cells via direct interaction between STAT3 and Sp1

“…Glial fibrillary acidic protein (GFAP)-IL-6 transgenic mice overexpressing IL-6 selectively in astrocytes 14 were a generous gift from Iain L. Campbell, The Scripps Research Institute, La Jolla, CA. VEGF-green fluorescent protein (GFP) mice carrying the reporter gene GFP under the control of the VEGF promoter 28 were contributed generously by Brian Seed, Massachusetts General Hospital, Boston, MA.…”

“…To study the transcriptional regulation of VEGF by IL-6 in vivo, we used GFAP-IL-6 transgenic mice overexpressing IL-6 in astrocytes 14 and crossbred them with VEGF-GFP reporter mice carrying the reporter gene GFP under the control of the human VEGF promoter. 28 In VEGF promoter activation, GFP is expressed and can be visualized in coronal sections using a fluorescence microscope.…”

“…IL-6 not only promotes the survival of certain neuronal cell populations 13 but also the reactive transformation of astrocytes. 14,15 The complex of IL-6 and its primary receptor, IL-6 receptor a (gp80), binds to the transmembrane signal transducer gp130 and activates gp130-associated janus kinases (JAKs) leading to the recruitment and phosphorylation of the signal transducer and activator of transcription 3 (STAT3). Active STAT3 dimerizes, translocates to the nucleus and binds to enhancer elements of target genes, thereby inducing transcriptional activation.…”

Metallothioneins Are Upregulated in Symptomatic Mice with Astrocyte-Targeted Expression of Tumor Necrosis Factor-α

“…Such alterations could presumably make an important contribution to the clinicopathological features of many neurological disorders, but the possibility that they are simply the consequence and not the cause must be ruled out experimentally. Results obtained in transgenic mice with astrocyte-targeted expression of cytokines such as IL-6 (5,6,8,12,14,31,52,60), IL-3 (13), IFN-␣ (1), and TNF-␣ (59) have unequivocally demonstrated that an abnormal cytokine production has the potential to cause devastating neurological disorders. Interestingly, each of these cytokines caused a specific repertoire of clinicopathological sequelae that presumably reflect the unique actions of the particular cytokine expressed.…”

Immuno- and genetic therapy in autoimmune diseases

“…Histological findings included astrocytosis, angiogenesis and neuro-degeneration. 28 IL-6 deficient (−/−) mice are resistant to myelin oligodendrocyte glycoprotein (MOG)-induced EAE. 29,30 This is not for lack of encephalitogenic cells as transfer of IL-6 +/+ T cells cannot induce disease consistent with IL-6 functioning at the perivascular inflammatory process.…”