Astrocyte expression of a dominant-negative interferon-γ receptor

Abstract

Interferon-γ (IFN-γ) is a major proinflammatory cytokine, and binding to its nearly ubiquitous receptor induces a wide variety of biological functions. To explore the role(s) of IFN-γ signaling in astrocytes, transgenic mice (GFAP/ IFN-γR1ΔIC) expressing a dominant-negative IFN-γ receptor alpha chain under control of the astrocyte-specific glial fibrillary acid protein (GFAP) promoter were generated. Transgenic mice developed normally, had normal astrocyte numbers and distribution, and exhibited no clinically overt phenotype. Transgene mRNA expression was detected only in the CNS, and the trans-gene-encoded IFN-γ receptor 1 colocalized with GFAR which is consistent with astrocyte expression. Astrocytes from transgenic mice exhibited reduced IFN-γ-induced signaling as measured by major histocompatibility class II induction. Neither CNS inflammation nor perforin-mediated clearance of a neurotropic mouse hepatitis virus from astrocytes was impaired following infection. Transgenic mice with impaired astrocyte responsiveness to IFN-γ provide a model for studying the selective astrocyte-dependent effects of this critical cytokine in CNS immunopathology. © 2005 Wiley-Liss, Inc.