Astrocytic Alterations in Interleukin-6/Soluble Interleukin-6 Receptor α Double-Transgenic Mice

Abstract

Interleukin-6 (IL-6), a major cytokine with diverse effects on cells mainly of the immune and hematopoietic systems, has been linked to several neurological disorders such as acquired immune deficiency syndrome dementia, multiple sclerosis, and Alzheimer's disease. Central nervous system (CNS)-specific expression of IL-6 caused neurodegeneration, massive gliosis, and vascular proliferation in transgenic mice. However, the effects of systemically circulating IL-6 and its receptor IL-6Ralpha on the CNS are unknown. IL-6Ralpha is the specific component of the IL-6 receptor system and hence an important co-factor of IL-6. IL-6Ralpha is bioactive in a membrane-bound and in a soluble (s) form. We investigated the effects of systemically elevated levels of either human IL-6 or human sIL-6Ralpha or both on the CNS of transgenic mice. Although IL-6 and sIL-6Ralpha single transgenic mice were free of neurological disease, IL-6/sIL-6Ralpha double-transgenic mice showed neurological signs, such as tremor, gait abnormalities, and paresis. However, these mice also frequently showed prominent general weakness probably because of the systemic effects of IL-6/IL-6Ralpha such as liver damage and plasmacytomas. IL-6/sIL-6Ralpha transgenic mice exhibited massive reactive gliosis. Lack of signs of neuronal breakdown versus ample astrogliosis suggested that astrocytes were selectively affected in these mice. There was neither vascular proliferation nor inflammatory infiltration. Ultrastructural analysis revealed blood-brain barrier (BBB) changes manifested by hydropic astrocytic end-feet. However, albumin immunohistochemistry did not reveal major BBB leakage. Our results indicate that increased and constitutive systemic expression of IL-6 together with its soluble receptor sIL-6Ralpha is less harmful to the brain than to other organs. The BBB remains primarily intact. IL-6/IL-6Ralpha, however, might be directly responsible for the selective activation of astrocytes.

IL-6 is required for glioma development in a mouse model

“…We showed previously that overexpression of IL-6 in transgenic mice leads to a severe reactive gliosis (Brunello et al, 2000), and others demonstrated that the absence of IL-6 impairs reactive astroglial transformation (Klein et al, 1997). However, this effect appears to be dependent on the type of lesion, as MPTP-induced astrogliosis is not impaired in mice lacking IL-6 (Cardenas and Bolin, 2003).…”

“…IL-6 is mitogenic for astrocytes (Selmaj et al, 1990), and, together with its soluble receptor (sIL-6Ra), induces a massive reactive gliosis in IL-6/sIL-6Ra double-transgenic mice (Brunello et al, 2000). CNS-specific expression of IL-6 causes lifelong gliosis in transgenic mice (Campbell et al, 1993).…”

Interleukin-6 and Diabetes

“…The action of IL-6 in type 1 diabetes pathogenesis may in principle be exerted at the level of the target ␤-cell, and/or at immune regulation, and/or at the hypothalamic-pituitary-adrenal axis. Several investigations of the putative impact of IL-6 on type 1 diabetes have been reported (8,(31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42) (Table 3). …”

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

“…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.…”