Astrocytic alterations in interleukin-6/soluble interleukin-6 receptor α double-transgenic mice

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-6R alpha on the CNS are unknown. IL-6R alpha is the specific component of the IL-6 receptor system and hence an important co-factor of IL-6, IL-6R alpha is bioactive in a membrane-bound and in a soluble Cs) form, We investigated the effects of systemically elevated levels of either human IL-6 or human sIL-6R alpha or both on the CNS of transgenic mice. Although IL-6 and sIL-6R alpha single transgenic mice were free of neurological disease, IL-6/sIL-6R alpha 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-6R alpha such as liver damage and plasmacytomas, IL-6/sIL-6R alpha 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-6R alpha is less harmful to the brain than to other organs. The BBB remains primarily intact. IL-6/IL-6R alpha, however, might be directly responsible for the selective activation of astrocytes.