title: STAT3 inhibitors attenuate interferon-γ-induced neurotoxicity and inflammatory molecule production by human astrocytes.
abstract: Activation of signal transducer and activator of transcription (STAT) 3 is observable in reactive astrocytes under certain neuropathological conditions. Interferon (IFN)-γ is shown to activate STAT3 in cultured rodent astrocytes. Here we investigated the effects of inhibiting STAT3 signaling on IFNγ-activated human astrocytes since we have recently demonstrated that human astrocytes become neurotoxic when stimulated by IFNγ. We found that 5'-deoxy-5'-(methylthio)adenosine (MTA) (300 μM), S3I-201 (10 μM), STAT3 inhibitor VII (3 μM) and JAK-inhibitor I (0.3 μM) had anti-neurotoxic effects on IFN-γ (50 U/ml)-activated astrocytes and U373-MG astrocytoma cells. Another inhibitor, AG490 (30 μM) had no significant effect. The active inhibitors also attenuated IFN-γ-induced phosphorylation of Tyr(705)-STAT3 and astrocytic expression of intercellular adhesion molecule-1 (ICAM-1). They also decreased astrocytic production of IFN-γ-inducible T cell α chemoattractant (I-TAC). AG490, which did not affect the Tyr(705)-STAT3 phosphorylation or ICAM-1 expression, nevertheless reduced the I-TAC secretion. Because these results indicate that pharmacological inhibition of STAT3 signaling correlates with reduced astrocytic neurotoxicity and ICAM-1 expression, but not that of I-TAC secretion, we consider that STAT3 activation mediates, at least in part, the IFN-γ-induced neurotoxicity and ICAM-1 expression by human astrocytes.
authors.affiliation: Kinsmen Laboratory of Neurological Research, Department of Psychiatry, The University of British Columbia, 2255 Wesbrook Mall, Vancouver, BC, Canada.
authors.forename: Sadayuki
authors.initials: S
authors.lastname: Hashioka
authors.forename: Andis
authors.initials: A
authors.lastname: Klegeris
authors.forename: Hong
authors.initials: H
authors.lastname: Qing
authors.forename: Patrick L
authors.initials: PL
authors.lastname: McGeer
mesh_terms: D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D002460:Cell Line; D045744:Cell Line, Tumor; D006801:Humans; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D007371:Interferon-gamma / Q000037:antagonists & inhibitors* / Q000502:physiology; D019636:Neurodegenerative Diseases / Q000378:metabolism* / Q000473:pathology*; D009498:Neurotoxins / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors*
chemical_list: D018836:Inflammation Mediators; D009498:Neurotoxins; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D018799:Intercellular Adhesion Molecule-1; D007371:Interferon-gamma