Astrocyte expression of a dominant-negative interferon-gamma receptor.
Interferon-gamma (IFN-gamma) 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-gamma signaling in astrocytes, transgenic mice (GFAP/IFN-gammaR1DeltaIC) expressing a dominant-negative IFN-gamma 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 transgene-encoded IFN-gamma receptor 1 colocalized with GFAP, which is consistent with astrocyte expression. Astrocytes from transgenic mice exhibited reduced IFN-gamma-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-gamma provide a model for studying the selective astrocyte-dependent effects of this critical cytokine in CNS immunopathology.
Hindinger
Claudia
C
Department of Neurology, University of Southern California, Keck School of Medicine, Los Angeles, California 90033, USA.
Gonzalez
John M
JM
Bergmann
Cornelia C
CC
Fuss
Babette
B
Hinton
David R
DR
Atkinson
Roscoe D
RD
Macklin
Wendy B
WB
Stohlman
Stephen A
SA
D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000378:metabolism*; D015152:Blotting, Northern / Q000379:methods; D001921:Brain / Q000166:cytology; D002478:Cells, Cultured; D005434:Flow Cytometry / Q000379:methods; D017353:Gene Deletion; D015870:Gene Expression / Q000187:drug effects / Q000502:physiology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D005904:Glial Fibrillary Acidic Protein / Q000235:genetics / Q000378:metabolism; D007150:Immunohistochemistry / Q000379:methods; D007371:Interferon-gamma / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009687:Nuclear Proteins / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D017471:Receptors, Interferon / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D015534:Trans-Activators / Q000378:metabolism; D014161:Transduction, Genetic / Q000379:methods; D000096743:Interferon gamma Receptor
D005904:Glial Fibrillary Acidic Protein; D007371:Interferon-gamma; D009687:Nuclear Proteins; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger; D017471:Receptors, Interferon; D015534:Trans-Activators; D000096743:Interferon gamma Receptor; C083728:MHC class II transactivator protein; C489428:Myc protein, mouse